Skip to main content

REVIEW article

Front. Microbiol., 11 September 2014
Sec. Microbial Immunology
This article is part of the Research Topic Why vaccines to HIV, HCV and Malaria have so far failed - challenges to developing vaccines against immunoregulating pathogens View all 14 articles

Targeting regulatory T cells to improve vaccine immunogenicity in early life

  • 1Infant Immunology Group, Vaccinology Theme, Medical Research Council Laboratories, Fajara, The Gambia
  • 2Vaccine and Infectious Diseases Laboratory, Department of Immunology, Monash University, Melbourne, VIC, Australia

Human newborns and infants are bombarded with multiple pathogens on leaving the sterile intra-uterine environment, and yet have suboptimal innate immunity and limited immunological memory, thus leading to increased susceptibility to infections in early life. They are thus the target age group for a host of vaccines against common bacterial and viral pathogens. They are also the target group for many vaccines in development, including those against tuberculosis (TB), malaria, and HIV infection. However, neonatal and infant responses too many vaccines are suboptimal, and in the case of the polysaccharide vaccines, it has been necessary to develop the alternative conjugated formulations in order to induce immunity in early life. Immunoregulatory factors are an intrinsic component of natural immunity necessary to dampen or control immune responses, with the caveat that they may also decrease immunity to infections or lead to chronic infection. This review explores the key immunoregulatory factors at play in early life, with a particular emphasis on regulatory T cells (Tregs). It goes on to explore the role that Tregs play in limiting vaccine immunogenicity, and describes animal and human studies in which Tregs have been depleted in order to enhance vaccine responses. A deeper understanding of the role that Tregs play in limiting or controlling vaccine-induced immunity would provide strategies to improve vaccine immunogenicity in this critical age group. New adjuvants and drugs are being developed that can transiently suppress Treg function, and their use as part of human vaccination strategies against infections is becoming a real prospect for the future.

Introduction

The infant immune system is uniquely adapted to meet the challenges of early life (Kollmann et al., 2012). The newborn emerges from an immune-protected environment into a world where they constantly encounter new antigens. There is therefore a need to have a series of immunoregulatory mechanisms in place in order to prevent excessive inflammation and tissue damage. At the same time the infant needs to develop immune memory upon pathogen encounter in order to be protected against future challenge. The newborn has little immunological memory, and neonates and infants are heavily reliant on innate immunity to protect them against antigenic challenge as discussed in a series of comprehensive review articles (Levy, 2007; Ghazal et al., 2013; Levy and Wynn, 2014).

In this review we discuss the regulatory factors that infants employ to suppress or control their developing immunity. We will focus on regulatory T cells (Tregs) in particular, and the potential role they play in suppressing or controlling vaccine-induced immunity in early life. We will explore the mechanisms of action used by Tregs to confer suppression, and differences in the phenotypic and functional characteristics between Tregs in infants and adults. We will discuss the role of Tregs in malaria, HIV, and hepatitis C virus (HCV) infections; and briefly describe the results of clinical trials in human infants of vaccines against these three infections. A detailed understanding of the immunoregulatory factors controlling vaccine immunogenicity in early life may provide potential strategies for improving vaccine efficacy in this vulnerable age group. We will discuss immunotherapeutic agents and vaccine adjuvants developed for use in humans that can down-modulate Treg activity and thus enhance vaccine efficacy, demonstrating that this approach is a viable option for the future.

The Infant Immune System

Innate Immunity

The innate immune system which acts as the first line of defense against infection is suboptimal at birth, and does not reach full capacity until teenage years. Innate cells express pattern recognition receptors (PRRs) which detect highly conserved pattern associate molecular patterns (PAMPs) expressed by invading pathogens or vaccines, including Toll-like receptors (TLRs) and NOD-like receptors (NLRs). Newborns and young infants have similar levels of expression of these PRRs as adults (Kollmann et al., 2012), however, responses to PRR stimulation are low at birth in part due to diminished innate signaling pathways such as IRF7 translocation (Danis et al., 2008) and TLR3 and 4 signaling (Aksoy et al., 2007). Reactivity to certain PRR agonists, e.g., TLR4 and TLR5 are acquired rapidly, and reactivity of the viral ssRNA sensing TLR7 and TLR8 receptors is robust from birth (Burl et al., 2011), hence TLR7/8 agonists are being investigated as possible adjuvants to boost immune responses to neonatal vaccines (Dowling et al., 2013). Th2 (IL-6, IL-10) and Th17 (IL-6, IL-23) polarizing cytokines dominate the innate response in early life, while TNF-α and IL-1β responses rise in the first few years of life as the former cytokines decline (Belderbos et al., 2009; Kollmann et al., 2009; Nguyen et al., 2010; Burl et al., 2011). Infant dendritic cell (DC) function is also suboptimal (De Wit et al., 2004; Goriely et al., 2004; Aksoy et al., 2007), and NK cells (Guilmot et al., 2011) and neutrophil functions (Carr, 2000) are less potent than in adults. Low complement levels in neonatal plasma are thought to increase susceptibility to certain bacterial infections, and lead to impaired adaptive immunity (Levy, 2007).

Adaptive Immunity in Infancy

Infant T cell immunity

The adaptive immune system is characterized by minimal immunological memory at birth, since the newborn has been relatively protected from antigenic exposure in utero, and most of their T cells are of a naïve phenotype. Furthermore, high levels of TGF-β, progesterone and prostaglandin E2 in utero required to prevent the mother developing Th1 alloreactivity to her fetus (Philbin and Levy, 2009), alongside poor innate Th1 support (Langrish et al., 2002), result in the newborn having intrinsically skewed Th2-type immunity from birth. Additionally, the Th17 biased innate immunity in infants also results in a Th17 adaptive bias. This bias against Th1 immunity results in an increased vulnerability to microbial infections and suboptimal reactivity to many vaccines. Despite this, infants have been shown to stimulate adult level Th1 type immune responses to BCG vaccination (Marchant et al., 1999) and are thus capable of robust Th1 immunity. However, neonatal BCG vaccination results in a Th17 biased mycobacterial response compared to those receiving BCG at 4½ months of age (Burl et al., 2010), in keeping with the Th17 bias described above.

Infant B cell immunity

Newborn infants acquire IgG antibodies transplacentally from their mothers which provide protection against infections encountered in early life, while the other immunoglobulin subclasses are unable to cross the maternal–placenta interface. The maternally acquired antibody (MAb) levels wane over the first 6 months of life and are usually absent by 1 year of age. Several studies suggest that MAbs inhibit humoral responses to infant vaccines; including live measles vaccine (Albrecht et al., 1977) and oral poliomyelitis vaccine, and non-live vaccines including pertussis (Burstyn et al., 1983; Englund et al., 1995), tetanus and diphtheria toxoids (Bjorkholm et al., 1995), Hib conjugate vaccine (Claesson et al., 1989; Daum et al., 1991) and hepatitis A vaccine (Kanra et al., 2000); while other studies report no influence of MAbs on responses to these vaccines (Gans et al., 1998; Siegrist et al., 1998; Sallusto et al., 1999). Responses may still be protective even if MAb inhibition occurs (Jones et al., 2014), and while MAbs may interfere with the generation of humoral responses to vaccination, T cell responses do not seem to be similarly affected (Siegrist, 2003).

Human neonatal antibody responses are delayed in onset, of shorter duration, achieve lower peak levels, and have lower affinity than adults. The isotype distribution also differs, with IgG1 and IgG2 levels peaking at ∼3–4 years of age, and IgG4 only reaching adult levels at 4–6 years of age, while IgG3 is stable from birth (Ngamphaiboon et al., 1998). Histological studies of infant splenic tissue show that the marginal zone does not reach full development until 2 years of age, which alongside low complement levels (Zandvoort and Timens, 2002; Kruetzmann et al., 2003) and low expression of CD21 (complement receptor 2; Griffioen et al., 1993), would account for the delayed antibody response to T cell independent glycoproteins and polysaccharide antigens, including encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae, and thus poor reactivity to polysaccharide vaccines (Adkins et al., 2004).

Immunoregulatory Factors in Neonatal and Infant Plasma

Neonatal and infant plasma contain a number of immunoregulatory factors that serve to maintain Th2 polarization, and limit pro-inflammatory innate and adaptive immunity. Newborns and infants have high levels of plasma adenosine, an endogenous purine metabolite with immunosuppressive properties. Adenosine causes mononuclear cells to produce cAMP, which acts as a second messenger to inhibit TLR-stimulated production of pro-inflammatory cytokines while polarizing toward IL-10 and Th17 cytokine production (Levy et al., 2006; Power Coombs et al., 2011; Philbin et al., 2012). Neonatal monocytes have increased sensitivity to these effects of adenosine via their adenosine A3 receptors, thus modulation of this system could potentially be used to enhance innate and therefore adaptive pro-inflammatory responses.

Several studies have shown that there are high levels of the immunosuppressive cytokine IL-10 in cord blood (CB; De Wit et al., 2004; Belderbos et al., 2009; Nguyen et al., 2010). IL-10 can be produced by most cell types of the immune system, including antigen presenting cells (APCs), granulocytes, and Th1, Th2 and many regulatory T cell subsets. IL-10 acts at a number of stages of an immune response in order to control inflammation. It inhibits the production of pro-inflammatory cytokines and chemokines by monocytes, macrophages and DCs, leading to increased IL-10 production by various T cell subsets. It suppresses both Th1 and the more recently described “Th1+Th17” cells, while enhancing CD4+FOXP3+ (forkhead box P3) regulatory T cell survival and activity, and promoting IgG and IgA class switching by B cells (Banchereau et al., 2012).

Human Regulatory T Cell Subtypes and their Modes of Action

Regulatory T cells are unique subpopulations of T cells that play a major role in immune homeostasis and tolerance (Sakaguchi, 2000; Belkaid et al., 2002; Mills and Mcguirk, 2004; Belkaid, 2007). Although Tregs have been shown to be beneficial in preventing an over-exuberant response and immune pathology following encounter with pathogens (Belkaid, 2008; Belkaid and Tarbell, 2009), they have also been shown to limit the favorable effector responses required for sterilizing immunity, thus allowing pathogen persistence (Kao et al., 2010).

Thymus Derived and Peripheral CD4+FOXP3+ Tregs

The Treg field was invigorated with the discovery of the transcription factor FOXP3 which is vital for the development, function and homeostasis of Tregs (Fontenot et al., 2003; Hori et al., 2003), and is thus considered the master regulator of Tregs. Its importance is further highlighted by patients with mutations in FOXP3 who develop a severe fatal disorder known as immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome (Bennett and Ochs, 2001; Gambineri et al., 2003).

Recently a group of experts in the Treg field introduced a consensus nomenclature for FOXP3+ Tregs. They suggest replacing previously used terms which they describe as being to some extent “inaccurate and ambiguous” (Abbas et al., 2013). They recommend that the subset of FOXP3+ Tregs of thymic origin, which are also known as natural Tregs (nTregs), should be called thymus-derived Tregs (tTregs); while FOXP3+ Tregs that differentiate in the periphery should be called peripherally derived Tregs (pTreg) rather than the previous term inducible Tregs (iTregs). The pTregs are induced in the periphery in response to antigenic stimulation, and possess identical characteristics to tTregs, and therefore both subsets will be described together.

Phenotype of human CD4+FOXP3+ Tregs

CD4+FOXP3+ Tregs are the most widely studied Treg subset. They were first described as a subset of CD4+ T cells which constitutively express the interleukin 2 (IL-2) receptor alpha-chains (CD25) and can prevent the development of autoimmunity in mice (Sakaguchi et al., 1995).

Determining the precise phenotype of human CD4+FOXP3+ Tregs has proved difficult with many conflicting studies. Since CD25 is transiently expressed on conventional T cells (Hatakeyama et al., 1989), the CD25hi subset is described as a more reliable marker of CD4+FOXP3+ Tregs in humans (Schmetterer et al., 2012). Human FOXP3+ Tregs also tend to express low levels of the IL-7 receptor CD127 (Liu et al., 2006; Seddiki et al., 2006). Therefore the most commonly analyzed phenotypes in human studies are CD4+CD25+FOXP3+ or CD4+CD25+CD127lo. Furthermore, human CD4+FOXP3+ Tregs generally express high levels of the co-inhibitory receptor cytotoxic T lymphocyte antigen 4 (CTLA4; Sansom and Walker, 2006). More recently the chemokine markers CCR4, CCR6, CXCR3, and CXCR10 have been proposed to define four distinct populations of human tTregs, each with distinct functional characteristics (Duhen et al., 2012). Each of these four Treg subsets are thought to co-localize in vivo with and regulate a distinct Th subset (Th1, Th2, Th17, Th22) expressing the same chemokine receptors.

CD45RA expression can be used to distinguish tTregs that are naïve or resting (rTregs; FOXP3loCD45RA+) from the memory subset described as activated Tregs (aTregs; FOXP3hiCD45RA-; Miyara et al., 2009). The memory Tregs can be further subdivided into central memory (TregCM) and effector memory (TregEM) similarly to Th cells, based on the expression of chemokine receptor 7 (CCR7; Sallusto et al., 1999; Tosello et al., 2008).

Certain subpopulations among CD4+FOXP3+ Tregs are more suppressive than others. For example, Tregs expressing the tumor necrosis factor receptor 2 (TNFRII) are thought to represent a highly suppressive CD4+FOXP3+ Treg subset (Minigo et al., 2009). Those CD4+CD25+FOXP3+ Tregs expressing the transmembrane cyclic ADP ribose hydrolase CD38 (mainly thymic derived and in the spleen) have particularly high suppressive activity in a murine model (Patton et al., 2011). CD38 is part of a cascade involved in the production of the immunosuppressive factor adenosine from NAD+ (Horenstein et al., 2013) which can have immunoregulatory properties as discussed earlier. Interestingly, the majority of infant T cells express CD38 (Scalzo-Inguanti and Plebanski, 2011), and as previously mentioned infants also have high plasma levels of adenosine, but a link between these two factors has yet to be explored in neonates and infants.

Mechanisms of CD4+FOXP3+ Treg mediated suppression

CD4+FOXP3+ Tregs can suppress the proliferation and activation of a multitude of immune cell types including T cells, NK and NKT cells, monocytes, macrophages, B cells, DCs, and eosinophils. They employ a variety of mechanisms to mediate this suppression, and are thought to be flexible in this respect by adapting their mechanism according to their local environment (reviewed by Wing and Sakaguchi, 2012). Both IL-2 and CTLA-4-dependent mechanisms have been described, with CD25 and CTLA-4 knockout mice having a similar phenotype to Foxp3 deficient mice (Wing and Sakaguchi, 2012). It is thought that the constitutive expression of CD25 by CD4+FOXP3+ Tregs allows them to consume the available IL-2, depriving effector T cells (Teffs) and leading to effector cell death (De La Rosa et al., 2004). Those tTregs expressing CTLA-4 can suppress T cell responses via down-modulation of CD28 signaling (Walker, 2013), and reduced co-stimulatory capacity of CD80/86 expressed by DCs (Wing et al., 2011).

A commonly used mechanism of Treg action is the production of soluble inhibitory factors, including either membrane bound or released immunosuppressive cytokines IL-10, TGF-β, and IL-35 (Collison et al., 2007). FOXP3+ Tregs can also generate high concentrations of adenosine (Mandapathil et al., 2010) which binds to the A2a receptor on immune cells activating an immunoinhibitory loop (Sitkovsky and Ohta, 2005) which results in inhibition of T cell proliferation and cytokine production (Raskovalova et al., 2005).

Type 1 Regulatory T Cells (tr1)

The Tr1 Tregs are a unique Treg subset that do not rely on the expression of high levels of CD25 or FOXP3 for their function (Levings and Roncarolo, 2000). They are activated in the periphery following antigenic stimulation in the presence of IL-10 (Groux et al., 1997; Vieira et al., 2004). Recently, lymphocyte-activation gene 3 (LAG3) and CD49b have been described to represent specific markers for Tr1 cells (Gagliani et al., 2013).

The Tr1 Tregs are known to produce high levels of the immunosuppressive cytokines IL-10 and TGF-β, some IL-5, low levels of IFN-γ and IL-2, and no IL-4 (Groux et al., 1997). The secretion of IL-10 is the main mechanism by which Tr1 cells are thought to mediate suppression. The IL-10 can be either free or membrane bound, and has been shown to suppress Teff proliferation/activation both directly and indirectly via a modulation of APC function (Roncarolo et al., 2006). They have also been shown to use cell–cell contact mechanisms (Gregori et al., 2012) and the production of granzyme B and perforin (Gregori et al., 2010) to mediate suppression.

T Helper Type 3 Cells (th3)

This unique subset of TGF-β producing Tregs was identified in early studies investigating oral tolerance. They have been shown to suppress the proliferation and activation of Th1 cells and suppress the development of autoimmunity in the mouse model of multiple sclerosis (Chen et al., 1994). They become activated in the periphery upon encounter with a specific antigen, and suppress via the production of the inhibitory cytokine TGF-β. Some studies show that Th3 cells may have a role to play in controlling autoimmunity and allergy in humans (Andersson et al., 2002; Perez-Machado et al., 2003), but the role that this subset plays in the maintenance of immune tolerance in humans is still not clearly defined.

CD8+ Tregs

While CD4+ Tregs have been widely studied in humans, CD8+ Tregs have not received the same attention. However, there is increasing evidence that subsets of CD8+ Tregs also play important immunoregulatory roles, and impaired CD8+ Treg function may lead to autoimmunity (Hu et al., 2004; Lu et al., 2008). The most widely described phenotype for CD8+ Tregs is CD25+CD28- (Ciubotariu et al., 1998; Filaci et al., 2004). Other markers include CD122, CTLA-4, GITR, CD38, CD103, and CD8αα (Uss et al., 2006; Simone et al., 2008; Smith and Kumar, 2008; Liu et al., 2014); a host of different CD8 Treg subsets have been described in humans expressing various combinations of these markers (Suzuki et al., 2012). While FOXP3 expression has been described in many CD8 Treg subsets, it may also represent an activation marker rather than acting as a regulatory factor since CD8+FOXP3+ cells have been found to be minimally suppressive in some studies (Mayer et al., 2011). Mechanisms of action of CD8+ Tregs that have been reported include cell–cell contact mediated suppression, secretion of the suppressive cytokines IL-10 and TGF-β, and induction of APC energy (Suzuki et al., 2008). CD8+CD45RA+CCR7+FOXP3+ cells may represent a discrete subset of CD8 Tregs which interfere with the TCR signaling cascade (Suzuki et al., 2012). More extensive work is required to better understand the origin and role of CD8+ Tregs in immunoregulation and autoimmunity, particularly in humans.

Phenotypic and Functional Differences Between Tregs in Infants Compared to Adults

Distinct qualitative and quantitative differences have been identified between the Tregs in adults and those of infants. Most of the studies in infants have analyzed Tregs in neonatal CB for comparison with adults, and different phenotypic markers have been used to characterize the Tregs in these studies contributing to some discrepancies in the results.

FOXP3+ Tregs have been found in much higher levels at birth compared to adults, whether defined as CD4+CD25+CD127lo (Nettenstrom et al., 2013) or CD4+CD25+FOXP3+ (Flanagan et al., 2010). Preterm infants have been shown to have higher levels still (Luciano et al., 2014). However, a study comparing CD4+CD25+CD127lo Tregs at different age groups, showed slight increases in Treg frequencies with age: 6.10% in CB; 7.22% in adults aged 20–25 years; and 7.5% in adults over the age of 60 years (Santner-Nanan et al., 2008); and another study found that neonates had similar number of cells expressing FOXP3 compared to their mothers, and a lower number of CD4+CD25bright cells (Ly et al., 2009). The reason for these conflicting results is not known.

Cord blood Tregs have been shown to be predominantly of the CD45RA+CD45RO- naïve phenotype in several studies (Kanegane et al., 1991; Wing et al., 2002; Takahata et al., 2004; Ly et al., 2009; Flanagan et al., 2010). Other phenotypic differences between cord and adult Tregs include the observation that CB Tregs are mostly CD27+ and thus at an earlier differentiation state than their mothers; they have a lower apoptotic potential as evidenced by lower CD95/Fas expression than their mothers; and less CD62L suggesting less of a TregCM lymph node homing phenotype (Flanagan et al., 2010). CB Tregs also express less CCR6 than their matched mothers, which is the chemokine receptor that characterizes the Th17- and Th22-like Tregs (Duhen et al., 2012). Since infants are Th2 biased then their Tregs should be predominantly of a CCR4+CCR6-CXCR3- Th2 Treg phenotype in keeping with the classification discussed previously (Duhen et al., 2012), although this has not been investigated in infants.

In vitro Treg suppression assays are difficult to perform in infants due to the lack of availability of large volumes of blood, combined with the low Treg frequencies in peripheral blood. Studies using CB are easier since large volumes are available for study. Several studies have shown that newborn CB Tregs are highly functional whereby they suppress T cell proliferation and IFN-γ production, further deviating from a Th1 response (Godfrey et al., 2005; Wing et al., 2005). Fan et al. (2012) found that CD4+CD25+ CB Tregs had a stronger immunosuppressive function than adult blood Tregs following two cycles of polyclonal stimulation. Mayer et al. (2012) found that CB CD4+CD25hi cells failed to suppress upon TCR activation whereas those freshly purified from adult blood did, but CB Tregs became strongly suppressive after antigen-specific stimulation. Another study found that low FOXP3 expression levels by CB Tregs correlated with minimal suppressive activity, but following expansion there was a significant increase in the suppressive activity of these CB Tregs with a shift from the CD45RA+ to the CD45RA- phenotype (Fujimaki et al., 2008). It has recently been shown that CB Tregs can be expanded more easily than adult peripheral blood Tregs, and CB Tregs are better suppressors in allogeneic mixed lymphocyte reactions than their adult counterparts (Lin et al., 2014).

Taken together these studies suggest distinct differences between infant and adult Tregs. Overall they seem to be present in higher frequencies than in adults, are more naïve and less differentiated, and are highly suppressive; all supporting an active immunoregulatory role in early life.

The Role of Tregs in Regulating Immunity to Malaria, HIV, and Hepatitis C Virus

Regulatory T cells have been implicated with an immunoregulatory role in both murine and human malaria infections (Scholzen et al., 2010). In mice, ablation of Foxp3+ Tregs led to increased T cell activation and decreased parasitaemia (Abel et al., 2012). In vivo depletion of Tregs protected mice from experimental cerebral malaria in a Plasmodium berghei model of infection (Wu et al., 2010). A FOXP3 promoter polymorphism in children has been associated with significant parasitaemia in a Congolese study suggesting a Treg role (Koukouikila-Koussounda et al., 2013). Malaria infected red blood cells (iRBCs) induced CD4+CD25hiFOXP3+ Tregs in vitro in healthy human volunteers (Scholzen et al., 2009). In human malaria sporozoite challenge experiments, Tregs have been shown to be induced rapidly after infection, and linked to lower pro-inflammatory cytokines and increased TGF-β production (Walther et al., 2005). Another study showed that malaria antigens can activate latent TGF-β on the surface of aTregs (Clemente et al., 2011). A study of 112 subjects in Kenya (infants to adults) found a correlation between the frequency of CD4+CD25hi T cells and increased risk of clinical malaria, suggesting Tregs may negatively affect natural immunity to malaria in humans (Todryk et al., 2008). In naturally exposed Gambians CD4+FOXP3+CD127lo Tregs during acute infection were inversely correlated with memory responses at 28 days, suggesting suppression of immune memory. In the same study, a CD4+FOXP3-CD45RO+ T cell population co-producing IFN-γ and IL-10 was more prevalent among children with uncomplicated malaria than those with severe disease, suggesting a beneficial immunoregulatory role for this IL-10 producing subset, presumably by limiting excessive inflammation (Walther et al., 2009). A role for the highly suppressive TNFRII+ Tregs in malaria parasite survival has been implicated in a study of Indonesian school children (Wammes et al., 2013). Overall, these data support an induction of Tregs during acute malaria infection which can limit the generation of immune memory and increase susceptibility to infection, but also control immunopathology and disease severity.

The role of Tregs in HIV infection remains poorly understood and the data are conflicting, in part due to the different phenotypes used to define Tregs in the various studies. However, the studies do support a regulatory role. For example, combination anti-retroviral therapy (cART) non-responders with persistent CD4 counts <200 cells/μL on therapy had higher peripheral blood Tregs and aTregs than cART responders, with higher IL-10+ Tregs and lower FOXP3 in lymphoid tissue (Gaardbo et al., 2014). Another longitudinal study also found higher numbers of Tregs associated with immunological non-responders defined as CD4 <500/μL (Saison et al., 2014). A study analyzing multiple Treg phenotypes in HIV infected individuals found evidence of Treg redistribution depending on HIV status (Serana et al., 2014). Untreated viraemic patients with stable CD4 counts had higher proportions of naïve Tregs with decreased TregCM compared to those on cART and healthy controls (Serana et al., 2014). The study suggests that effective cART restores Treg homeostasis since Treg subpopulations in the cART group were similar to those of healthy donors. Increased proportions and decreased numbers of Tregs associate with progression of HIV (Wang et al., 2013). Treg depletion in a murine chronic retrovirus infection model resulted in reduced viral loads (Dietze et al., 2013). In combination, the data suggest that Tregs may suppress HIV-specific immunity leading to lower CD4 counts and viral persistence.

Hepatitis C virus is characterized by its ability to establish chronic infection in the majority of those infected, and an immunoregulatory role for Tregs in this process has been well described. Chronic HCV patients have increased levels of CD4+ and Tr1 Tregs in peripheral blood which are thought to suppress anti-viral T cell responses leading to viral persistence (Chang, 2007). Certain HCV epitope variants have been shown to induce Tregs in HCV-infected patients (Cusick et al., 2011). Chronic HCV patients have more serum IL-10 than those with resolved infection, which is proposed to play a role in the induction of CD4+FOXP3+ Tregs in chronic HCV infection (Macdonald et al., 2002; Cusick et al., 2013); and CD49b, a marker for IL-10 producing Tr1 Treg cells, is lower in those who respond to viral therapy, thus suggesting a regulatory role for Tr1 Tregs too (Fabien et al., 2014). Indoleamine 2,3-dioxygenase (IDO) production by stimulated monocyte derived DCs was higher in HCV patients compared to healthy controls, and these DCs were more able to induce Tregs, suggesting a role for this Treg induction pathway in chronic HCV (Higashitani et al., 2013). Expression of the inhibitory signaling pathway molecule T cell immunoglobulin and mucin-domain-protein-3 (Tim-3) is upregulated on both Teff and CD4+CD25+FOXP3+ Tregs in chronic HCV, correlating with increased Treg and decreased Teff proliferation, suggesting that the Tim-3 pathway controls the Treg/Teff balance in chronic HCV (Moorman et al., 2012). Viral persistence following acute HCV infection is accompanied by increased plasma Galectin-9 (Gal-9) which is the ligand for Tim-3, alongside expanded Gal-9 expressing Tregs and increased expression of Tim-3 and CTLA-4 on HCV-specific CD8+ T cells (Kared et al., 2013). Thus high levels of Tregs likely contribute to viral persistence in HCV infection, and both FOXP3+ and Tr1 Tregs have been implicated. Mechanisms of Treg induction in HCV may be multifactorial but include HCV antigen driven induction, IL-10, IDO, Gal-9/Tim-3, and CTLA-4.

Role of Tregs in Controlling Vaccine Immunogenicity

The role that Tregs play in controlling or limiting vaccine immunogenicity remains to be fully determined. Given that Tregs are induced by natural infections to regulate the inflammatory response, it makes sense that Tregs would be induced as part of the immune response to vaccination, particularly for live attenuated vaccines. One might predict that their induction would play a beneficial immunoregulatory role by preventing an over-exuberant immune response to the vaccine. However, most studies suggest that Tregs can interfere with the generation of vaccine-induced immunity. Thus, depletion of Tregs pre-vaccination in murine models has been shown to enhance immune responses to some vaccines. In a DEREG mouse model, which allows for in vivo depletion of Foxp3+ Treg cells at any point during an immune response using diphtheria toxin (Lahl and Sparwasser, 2011), Treg depletion led to an enhanced anti-tumor response to vaccination against an established melanoma (Klages et al., 2010). A more recent study showed that the short term depletion of Tregs in DEREG mice greatly enhanced vaccine-induced immunity against a solid tumor; increasing NK cells and CD8 T cell activation and IFN-γ production (Mattarollo et al., 2013). Administration of vaccines with anti-CD25 monoclonal Ab has been shown to induce more durable immunity in mice compared to when the vaccine is administered alone, for both BCG and hepatitis B vaccines, which has been attributed to a depletion of CD25+ Tregs (Moore et al., 2005). Ho et al. (2010) showed that antigen-specific Tregs induced by environmental mycobacteria suppress Th1 immune responses, thus compromising the response to BCG vaccination in mice. They also showed a correlation between the pre-existing Tregs and the subsequent vaccine response. Murine studies of Parkinson’s disease have shown that Tregs are induced by BCG vaccination (Lacan et al., 2013).

It is difficult to translate these studies into primates and humans since murine Tregs are not phenotypically identical, and in vivo depletion of FOXP3+ Tregs in healthy humans presents logistic and ethical challenges. An oral vaccine against simian immunodeficiency virus (SIV) based on a Lactobacillus commensal that favors immune tolerance induction was used to induce T cell tolerance to SIV antigens in macaques (Lu et al., 2012). The vaccine-induced CD8+ Tregs that suppressed CD4+ T cell activation and ex vivo SIV replication, and provided sterile protection against an intrarectal SIV challenge in 15 of 16 vaccinated macaques. This strategy is thought to work because CD4+ T cell activation drives the initial phase of viral replication, and provides the proof-of-concept that an oral Treg inducing vaccine could prevent the establishment of HIV infection.

Using a DC-based vaccine in HIV patients undergoing cART, it was shown that depletion of the Tregs in vitro significantly enhanced the vaccine-induced anti-HIV-1-specific polyfunctional T cell response, suggesting that Tregs can dampen vaccine-induced immunity (Macatangay et al., 2010). This study also showed a marked increase in the CD4+CD25hiFOXP3+ Treg numbers following vaccination, however, this increase did not correlate with the effector CD8+ T cell vaccine-induced response. Increased FOXP3 mRNA expression has been demonstrated in malaria vaccinated adults; however, the authors concluded that this might be attributed to the participants being naturally exposed to the malaria parasite rather than as a result of vaccination per se (Mwacharo et al., 2009).

Very few studies have looked at the role that Tregs play in controlling vaccine immunogenicity in infants. Our group found no correlation between PPD-specific CD4+CD25+FOXP3+ Tregs or CD4+IL-10+ Tregs, or PPD stimulated total IL-10 production on the day of BCG vaccination of Gambian infants, and subsequent IFN-γ responses to PPD (Burl et al., 2010). No functional Treg assays were conducted in this study. In another study we found that placental associated malaria (PAM) infection is associated with increased malaria-specific CD4+CD25+FOXP3+ Tregs (Flanagan et al., 2010) and that PAM also correlates with decreased immunogenicity of BCG vaccination as evidenced by poorer PPD reactivity persisting to 1 year of age compared to PAM negative children (Walther et al., 2012). Whether the Tregs are the cause of this attenuation of BCG responses is not known.

Targeting Tregs in Vivo to Enhance Vaccine Immunogenicity

The cancer research field has made considerable advances in dissecting the role that Tregs play in cancer progression and their role in suppressing responses to cancer vaccines. Moreover, trials conducted in animal models and humans have demonstrated that certain drugs and immunotherapies can transiently decrease Treg frequencies in vivo leading to improved anti-tumor Teff functions, and in some cases reduced tumor load. Since Treg depletion can enhance inflammation and autoimmunity then such transient depletion, as opposed to long term effects, is desirable. In low doses, the agent cyclophosphamide transiently decreases Treg frequencies while Teff functions are preserved, leading to enhanced responses to vaccine antigens and improved vaccine immunogenicity in mouse and human cancer vaccine trials (Barbon et al., 2010; Le and Jaffee, 2012). Anti-CD25 monoclonal antibodies, which deplete Tregs in vivo, enhanced vaccine efficacy in mouse models of pancreatic carcinoma (Keenan et al., 2014) and melanoma (Tan et al., 2013). Basiliximab and Daclizumab are anti-human CD25 MAbs that cause both decreased number and decreased function of Tregs by blocking IL-2 signaling (Goebel et al., 2000; Kohm et al., 2006; Mitchell et al., 2011). Daclizumab has been used in several human breast cancer vaccine trials where it depleted Tregs and improved effector responses, and furthermore may reprogram naïve Tregs to become IFN-γ producers (Rech and Vonderheide, 2009; Rech et al., 2012). The human monoclonal antibody, Ipilimumab, inhibits Tregs by blocking CTLA-4; and was approved by the FDA in 2011 for use in melanoma patients (Peggs et al., 2009).

Certain innate agonists that are being used as vaccine adjuvants preferentially expand Teff over Tregs, e.g., the TLR3 agonist Poly(I:C) and the TLR9 agonist CpG-ODN; whereas others favor Treg expansion, e.g., the TLR7 agonist imiquimod (Perret et al., 2013). OX40 is part of the TNFR superfamily expressed by Teff and Tregs, and the monoclonal antibody increases Teff function while blocking Treg function. OX40 clones have been humanized as potential agents to enhance the immunogenicity of vaccines against infectious diseases (Voo et al., 2013).

An interesting approach is that of local depletion of Tregs at the site of injection of a vaccine. Chemokine receptor 4 (CCR4) antagonists can be used as vaccine adjuvants to target and decrease local recruitment of CCR4+ Tregs in order to amplify vaccine responses at the site of immunization (Bayry, 2014).

Therefore a number of agents that target Tregs are being used experimentally in humans in order to enhance vaccine efficacy. Some of these are non-toxic and safe for use in humans, offering the future prospect of using this approach to enhance immunogenicity of vaccines against infectious diseases including malaria, HIV, and HCV.

Trials of Novel Vaccines Against Malaria, HIV, and HCV in Infants

Despite the multiple obstacles to successful infant vaccination discussed above, many vaccines are currently delivered in infancy with good immunogenicity, including the live BCG, measles and yellow fever vaccines; and the inactivated diphtheria, tetanus, pertussis and hepatitis B vaccines, H. influenzae b, and pneumococcal conjugate vaccine. The RTS,S/AS01 malaria vaccine is the most advanced malaria vaccine in human clinical trials, having reached phase III testing in children and infants, with potential licensure in 2015. It reduced clinical and severe malaria by 56 and 47.3% respectively in children aged 5–17 months (Bejon et al., 2008; Olotu et al., 2011); but only 31.3 and 36.6% when administered in three doses with routine Expanded Program on Immunization (EPI) vaccines in the 6–12 week old age group (Rts et al., 2012). Follow up of the 5–17 month old vaccinated group over a 4 year period found protection waned to 16.8%; with waning greater among those with higher malaria exposure suggesting that natural immunity to malaria contributes to the waning (Olotu et al., 2013). Whether exposure induced Tregs play a role in this waning has not been investigated.

Fowlpox and modified vaccinia Ankara (MVA) based malaria vaccines have been tested in 1–6 year olds with no evidence of protective efficacy (Bejon et al., 2007). A blood stage vaccine FMP2.1/AS02A has been tested in Malian children aged 1–6 years with an efficacy of <10% (Laurens et al., 2013). The blood stage alum adjuvanted GMZ2 malaria vaccine elicited good inhibitory antibody levels in pre-school children (Jepsen et al., 2013). Prime-boost strategies based on chimp adenovirus vector priming followed by MVA boosting are being tested in children and infants in Africa, and while results of these trials are not yet available the adult studies have shown unprecedented immunogenicity for malaria exposed populations (Ogwang et al., 2013) and should stimulate good immunity in infants.

Only a few human HIV vaccine trials have been conducted in healthy uninfected and HIV-exposed infants. Immunogenicity was limited among healthy Gambian infants given a single dose of MVA.HIVA, but this was not surprising given that MVA alone is known to be poorly immunogenic (Afolabi et al., 2013). In a Ugandan trial, infants were vaccinated at birth, 4, 8, and 12 weeks of age with ALVAC-HIV vCP1521 (ALVAC) candidate HIV vaccine which induced low level CD4 and CD8 T cell responses at 24 months (Kaleebu et al., 2014).

The target population for HCV vaccines include intravenous drug abusers and health care professionals. However, HCV infection is common throughout the world and mother-to-child transmission is well described (Yeung et al., 2001). Thus an infant HCV vaccine would have its place, particularly in resource poor settings where the anti-viral therapies available are currently not affordable. Both therapeutic and prophylactic vaccines are being developed, and several have now entered phase I/II human clinical trials, mostly of therapeutic vaccines in chronically infected cohorts. These include recombinant protein, peptide, DNA, and vector-based vaccines aimed at producing robust anti-T cell responses (Halliday et al., 2011). As far as we are aware no HCV vaccine trials have been conducted in children.

Future Prospects

There is very little in the literature regarding the role of Tregs in infants in general, and even less in respect to vaccine immunogenicity. The fact that functional Tregs are present in high numbers in infancy and have potent suppressive activity, coupled with poor immunological responses to some vaccines in this vulnerable age group, supports a need to better understand the role they play in controlling the response to childhood vaccines in particular. The data available suggest that Tregs suppress immunity to vaccines, and that they can also be induced by vaccination. We have shown that malaria, HIV, and HCV all use Tregs to evade host immune responses, therefore vaccine-induced Tregs would be predicted to reduce the protective efficacy of vaccines against these infections. A better understanding of the role that Tregs and other immunoregulatory factors play in contributing to poor vaccine immunogenicity in childhood would help with the design of better vaccines. Studies in cancer patients have shown that transient Treg inactivation or depletion is a viable approach to enhancing vaccine efficacy. A number of Treg modifying agents are available for use in humans, therefore this approach is a very real prospect for the future and may be particularly applicable to neonates and infants.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

Abbas, A. K., Benoist, C., Bluestone, J. A., Campbell, D. J., Ghosh, S., Hori, S.,et al. (2013). Regulatory T cells: recommendations to simplify the nomenclature. Nat. Immunol. 14, 307–308. doi: 10.1038/ni.2554

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Abel, S., Luckheide, N., Westendorf, A. M., Geffers, R., Roers, A., Muller, W.,et al. (2012). Strong impact of CD4+ Foxp3+ regulatory T cells and limited effect of T cell-derived IL-10 on pathogen clearance during Plasmodium yoelii infection. J. Immunol. 188, 5467–5477. doi: 10.4049/jimmunol.1102223

CrossRef Full Text

Adkins, B., Leclerc, C., and Marshall-Clarke, S. (2004). Neonatal adaptive immunity comes of age. Nat. Rev. Immunol. 4, 553–564. doi: 10.1038/nri1394

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Afolabi, M. O., Ndure, J., Drammeh, A., Darboe, F., Mehedi, S. R., Rowland-Jones, S. L.,et al. (2013). A phase I randomized clinical trial of candidate human immunodeficiency virus type 1 vaccine MVA.HIVA administered to Gambian infants. PLoS ONE 8:e78289. doi: 10.1371/journal.pone.0078289

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Aksoy, E., Albarani, V., Nguyen, M., Laes, J. F., Ruelle, J. L., De Wit, D.,et al. (2007). Interferon regulatory factor 3-dependent responses to lipopolysaccharide are selectively blunted in cord blood cells. Blood 109, 2887–2893. doi: 10.1182/blood-2006-06-027862

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Albrecht, P., Ennis, F. A., Saltzman, E. J., and Krugman, S. (1977). Persistence of maternal antibody in infants beyond 12 months: mechanism of measles vaccine failure. J. Pediatr. 91, 715–718. doi: 10.1016/S0022-3476(77)81021-4

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Andersson, P. O., Olsson, A., and Wadenvik, H. (2002). Reduced transforming growth factor-beta1 production by mononuclear cells from patients with active chronic idiopathic thrombocytopenic purpura. Br. J. Haematol. 116, 862–867. doi: 10.1046/j.0007-1048.2002.03345.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Banchereau, J., Pascual, V., and O’Garra, A. (2012). From IL-2 to IL-37: the expanding spectrum of anti-inflammatory cytokines. Nat. Immunol. 13, 925–931. doi: 10.1038/ni.2406

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Barbon, C. M., Yang, M., Wands, G. D., Ramesh, R., Slusher, B. S., Hedley, M. L.,et al. (2010). Consecutive low doses of cyclophosphamide preferentially target Tregs and potentiate T cell responses induced by DNA PLG microparticle immunization. Cell. Immunol. 262, 150–161. doi: 10.1016/j.cellimm.2010.02.007

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Bayry, J. (2014). Regulatory T cells as adjuvant target for enhancing the viral disease vaccine efficacy. Virusdisease 25, 18–25. doi: 10.1007/s13337-013-0187-3

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Bejon, P., Lusingu, J., Olotu, A., Leach, A., Lievens, M., Vekemans, J.,et al. (2008). Efficacy of RTS,S/AS01E vaccine against malaria in children 5 to 17 months of age. N. Engl. J. Med. 359, 2521–2532. doi: 10.1056/NEJMoa0807381

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Bejon, P., Ogada, E., Mwangi, T., Milligan, P., Lang, T., Fegan, G.,et al. (2007). Extended follow-up following a phase 2b randomized trial of the candidate malaria vaccines FP9 ME-TRAP and MVA ME-TRAP among children in Kenya. PLoS ONE 2:e707. doi: 10.1371/journal.pone.0000707

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Belderbos, M. E., Van Bleek, G. M., Levy, O., Blanken, M. O., Houben, M. L., Schuijff, L.,et al. (2009). Skewed pattern of Toll-like receptor 4-mediated cytokine production in human neonatal blood: low LPS-induced IL-12p70 and high IL-10 persist throughout the first month of life. Clin. Immunol. 133, 228–237. doi: 10.1016/j.clim.2009.07.003

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Belkaid, Y. (2007). Regulatory T cells and infection: a dangerous necessity. Nat. Rev. Immunol. 7, 875–888. doi: 10.1038/nri2189

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Belkaid, Y. (2008). Paradoxical roles of Foxp3+ T cells during infection: from regulators to regulators. Cell Host Microbe 3, 341–343. doi: 10.1016/j.chom.2008.05.011

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Belkaid, Y., Piccirillo, C. A., Mendez, S., Shevach, E. M., and Sacks, D. L. (2002). CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420, 502–507. doi: 10.1038/nature01152

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Belkaid, Y., and Tarbell, K. (2009). Regulatory T cells in the control of host-microorganism interactions (*). Annu. Rev. Immunol. 27, 551–589. doi: 10.1146/annurev.immunol.021908.132723

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Bennett, C. L., and Ochs, H. D. (2001). IPEX is a unique X-linked syndrome characterized by immune dysfunction, polyendocrinopathy, enteropathy, and a variety of autoimmune phenomena. Curr. Opin. Pediatr. 13, 533–538. doi: 10.1097/00008480-200112000-00007

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Bjorkholm, B., Granstrom, M., Taranger, J., Wahl, M., and Hagberg, L. (1995). Influence of high titers of maternal antibody on the serologic response of infants to diphtheria vaccination at three, five and twelve months of age. Pediatr. Infect. Dis. J. 14, 846–850. doi: 10.1097/00006454-199510000-00005

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Burl, S., Adetifa, U. J., Cox, M., Touray, E., Ota, M. O., Marchant, A.,et al. (2010). Delaying Bacillus Calmette-Guerin vaccination from birth to 4 1/2 months of age reduces postvaccination Th1 and IL-17 responses but leads to comparable mycobacterial responses at 9 months of age. J. Immunol. 185, 2620–2628. doi: 10.4049/jimmunol.1000552

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Burl, S., Townend, J., Njie-Jobe, J., Cox, M., Adetifa, U. J., Touray, E.,et al. (2011). Age-dependent maturation of Toll-like receptor-mediated cytokine responses in Gambian infants. PLoS ONE 6:e18185. doi: 10.1371/journal.pone.0018185

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Burstyn, D. G., Baraff, L. J., Peppler, M. S., Leake, R. D., St Geme, J. Jr., and Manclark, C. R. (1983). Serological response to filamentous hemagglutinin and lymphocytosis-promoting toxin of Bordetella pertussis. Infect. Immun. 41, 1150–1156.

Pubmed Abstract | Pubmed Full Text

Carr, R. (2000). Neutrophil production and function in newborn infants. Br. J. Haematol. 110, 18–28. doi: 10.1046/j.1365-2141.2000.01992.x

CrossRef Full Text

Chang, K. M. (2007). Regulatory T cells in hepatitis C virus infection. Hepatol. Res. 37(Suppl. 3), S327–S330. doi: 10.1111/j.1872-034X.2007.00220.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Chen, Y., Kuchroo, V. K., Inobe, J., Hafler, D. A., and Weiner, H. L. (1994). Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265, 1237–1240. doi: 10.1126/science.7520605

CrossRef Full Text

Ciubotariu, R., Colovai, A. I., Pennesi, G., Liu, Z., Smith, D., Berlocco, P.,et al. (1998). Specific suppression of human CD4+ Th cell responses to pig MHC antigens by CD8+CD28- regulatory T cells. J. Immunol. 161, 5193–5202.

Claesson, B. A., Schneerson, R., Robbins, J. B., Johansson, J., Lagergard, T., Taranger, J.,et al. (1989). Protective levels of serum antibodies stimulated in infants by two injections of Haemophilus influenzae type b capsular polysaccharide-tetanus toxoid conjugate. J. Pediatr. 114, 97–100. doi: 10.1016/S0022-3476(89)80611-0

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Clemente, A., Caporale, R., Sannella, A. R., Majori, G., Severini, C., Fadigati, G.,et al. (2011). Plasmodium falciparum soluble extracts potentiate the suppressive function of polyclonal T regulatory cells through activation of TGFbeta-mediated signals. Cell. Microbiol. 13, 1328–1338. doi: 10.1111/j.1462-5822.2011.01622.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Collison, L. W., Workman, C. J., Kuo, T. T., Boyd, K., Wang, Y., Vignali, K. M.,et al. (2007). The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566–569. doi: 10.1038/nature06306

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Cusick, M. F., Libbey, J. E., Cox Gill, J., Fujinami, R. S., and Eckels, D. D. (2013). CD4+ T-cell engagement by both wild-type and variant HCV peptides modulates the conversion of viral clearing helper T cells to Tregs. Future Virol. 8. doi: 10.2217/fvl.13.49

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Cusick, M. F., Schiller, J. J., Gill, J. C., and Eckels, D. D. (2011). Hepatitis C virus induces regulatory T cells by naturally occurring viral variants to suppress T cell responses. Clin. Dev. Immunol. 2011:806061. doi: 10.1155/2011/806061

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Danis, B., George, T. C., Goriely, S., Dutta, B., Renneson, J., Gatto, L.,et al. (2008). Interferon regulatory factor 7-mediated responses are defective in cord blood plasmacytoid dendritic cells. Eur. J. Immunol. 38, 507–517. doi: 10.1002/eji.200737760

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Daum, R. S., Siber, G. R., Ballanco, G. A., and Sood, S. K. (1991). Serum anticapsular antibody response in the first week after immunization of adults and infants with the Haemophilus influenzae type b-Neisseria meningitidis outer membrane protein complex conjugate vaccine. J. Infect. Dis. 164, 1154–1159. doi: 10.1093/infdis/164.6.1154

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

De La Rosa, M., Rutz, S., Dorninger, H., and Scheffold, A. (2004). Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur. J. Immunol. 34, 2480–2488. doi: 10.1002/eji.200425274

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

De Wit, D., Olislagers, V., Goriely, S., Vermeulen, F., Wagner, H., Goldman, M.,et al. (2004). Blood plasmacytoid dendritic cell responses to CpG oligodeoxynucleotides are impaired in human newborns. Blood 103, 1030–1032. doi: 10.1182/blood-2003-04-1216

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Dietze, K. K., Zelinskyy, G., Liu, J., Kretzmer, F., Schimmer, S., and Dittmer, U. (2013). Combining regulatory T cell depletion and inhibitory receptor blockade improves reactivation of exhausted virus-specific CD8+ T cells and efficiently reduces chronic retroviral loads. PLoS Pathog. 9:e1003798. doi: 10.1371/journal.ppat.1003798

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Dowling, D. J., Tan, Z., Prokopowicz, Z. M., Palmer, C. D., Matthews, M. A., Dietsch, G. N.,et al. (2013). The ultra-potent and selective TLR8 agonist VTX-294 activates human newborn and adult leukocytes. PLoS ONE 8:e58164. doi: 10.1371/journal.pone.0058164

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Duhen, T., Duhen, R., Lanzavecchia, A., Sallusto, F., and Campbell, D. J. (2012). Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells. Blood 119, 4430–4440. doi: 10.1182/blood-2011-11-392324

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Englund, J. A., Anderson, E. L., Reed, G. F., Decker, M. D., Edwards, K. M., Pichichero, M. E.,et al. (1995). The effect of maternal antibody on the serologic response and the incidence of adverse reactions after primary immunization with acellular and whole-cell pertussis vaccines combined with diphtheria and tetanus toxoids. Pediatrics 96, 580–584.

Pubmed Abstract | Pubmed Full Text

Fabien, S., Olivier, M., Khaldoun, G., Vivian, V., Lynda, A., Laurissa, O.,et al. (2014). CD49b, a major marker of regulatory T-cells type 1, predicts the response to antiviral therapy of recurrent hepatitis C after liver transplantation. Biomed Res. Int. 2014:290878. doi: 10.1155/2014/290878

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Fan, H., Yang, J., Hao, J., Ren, Y., Chen, L., Li, G.,et al. (2012). Comparative study of regulatory T cells expanded ex vivo from cord blood and adult peripheral blood. Immunology 136, 218–230. doi: 10.1111/j.1365-2567.2012.03573.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Filaci, G., Fravega, M., Negrini, S., Procopio, F., Fenoglio, D., Rizzi, M.,et al. (2004). Nonantigen specific CD8+ T suppressor lymphocytes originate from CD8+CD28- T cells and inhibit both T-cell proliferation and CTL function. Hum. Immunol. 65, 142–156. doi: 10.1016/j.humimm.2003.12.001

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Flanagan, K. L., Halliday, A., Burl, S., Landgraf, K., Jagne, Y. J., Noho-Konteh, F.,et al. (2010). The effect of placental malaria infection on cord blood and maternal immunoregulatory responses at birth. Eur. J. Immunol. 40, 1062–1072. doi: 10.1002/eji.200939638

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Fontenot, J. D., Gavin, M. A., and Rudensky, A. Y. (2003). Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336. doi: 10.1038/ni904

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Fujimaki, W., Takahashi, N., Ohnuma, K., Nagatsu, M., Kurosawa, H., Yoshida, S.,et al. (2008). Comparative study of regulatory T cell function of human CD25CD4 T cells from thymocytes, cord blood, and adult peripheral blood. Clin. Dev. Immunol. 2008:305859. doi: 10.1155/2008/305859

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Gaardbo, J. C., Hartling, H. J., Ronit, A., Springborg, K., Gjerdrum, L. M., Ralfkiaer, E.,et al. (2014). Regulatory T cells in HIV-infected immunological non-responders are increased in blood but depleted in lymphoid tissue and predict immunological reconstitution. J. Acquir. Immune Defic. Syndr. 66, 349–357. doi: 10.1097/QAI.0000000000000173

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Gagliani, N., Magnani, C. F., Huber, S., Gianolini, M. E., Pala, M., Licona-Limon, P.,et al. (2013). Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat. Med. 19, 739–746. doi: 10.1038/nm.3179

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Gambineri, E., Torgerson, T. R., and Ochs, H. D. (2003). Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr. Opin. Rheumatol. 15, 430–435. doi: 10.1097/00002281-200307000-00010

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Gans, H. A., Arvin, A. M., Galinus, J., Logan, L., Dehovitz, R., and Maldonado, Y. (1998). Deficiency of the humoral immune response to measles vaccine in infants immunized at age 6 months. JAMA 280, 527–532. doi: 10.1001/jama.280.6.527

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ghazal, P., Dickinson, P., and Smith, C. L. (2013). Early life response to infection. Curr. Opin. Infect. Dis. 26, 213–218. doi: 10.1097/QCO.0b013e32835fb8bf

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Godfrey, W. R., Spoden, D. J., Ge, Y. G., Baker, S. R., Liu, B., Levine, B. L.,et al. (2005). Cord blood CD4(+)CD25(+)-derived T regulatory cell lines express FoxP3 protein and manifest potent suppressor function. Blood 105, 750–758. doi: 10.1182/blood-2004-06-2467

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Goebel, J., Stevens, E., Forrest, K., and Roszman, T. L. (2000). Daclizumab (Zenapax) inhibits early interleukin-2 receptor signal transduction events. Transpl. Immunol. 8, 153–159. doi: 10.1016/S0966-3274(00)00021-6

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Goriely, S., Van Lint, C., Dadkhah, R., Libin, M., De Wit, D., Demonte, D.,et al. (2004). A defect in nucleosome remodeling prevents IL-12(p35) gene transcription in neonatal dendritic cells. J. Exp. Med. 199, 1011–1016. doi: 10.1084/jem.20031272

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Gregori, S., Goudy, K. S., and Roncarolo, M. G. (2012). The cellular and molecular mechanisms of immuno-suppression by human type 1 regulatory T cells. Front. Immunol. 3:30. doi: 10.3389/fimmu.2012.00030

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Gregori, S., Tomasoni, D., Pacciani, V., Scirpoli, M., Battaglia, M., Magnani, C. F.,et al. (2010). Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway. Blood 116, 935–944. doi: 10.1182/blood-2009-07-234872

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Griffioen, A. W., Franklin, S. W., Zegers, B. J., and Rijkers, G. T. (1993). Expression and functional characteristics of the complement receptor type 2 on adult and neonatal B lymphocytes. Clin. Immunol. Immunopathol. 69, 1–8. doi: 10.1006/clin.1993.1142

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Groux, H., O’Garra, A., Bigler, M., Rouleau, M., Antonenko, S., De Vries, J. E.,et al. (1997). A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742. doi: 10.1038/39614

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Guilmot, A., Hermann, E., Braud, V. M., Carlier, Y., and Truyens, C. (2011). Natural killer cell responses to infections in early life. J. Innate Immun. 3, 280–288. doi: 10.1159/000323934

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Halliday, J., Klenerman, P., and Barnes, E. (2011). Vaccination for hepatitis C virus: closing in on an evasive target. Expert Rev. Vaccines 10, 659–672. doi: 10.1586/erv.11.55

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Hatakeyama, M., Tsudo, M., Minamoto, S., Kono, T., Doi, T., Miyata, T.,et al. (1989). Interleukin-2 receptor beta chain gene: generation of three receptor forms by cloned human alpha and beta chain cDNA’s. Science 244, 551–556. doi: 10.1126/science.2785715

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Higashitani, K., Kanto, T., Kuroda, S., Yoshio, S., Matsubara, T., Kakita, N.,et al. (2013). Association of enhanced activity of indoleamine 2,3-dioxygenase in dendritic cells with the induction of regulatory T cells in chronic hepatitis C infection. J. Gastroenterol. 48, 660–670. doi: 10.1007/s00535-012-0667-z

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ho, P., Wei, X., and Seah, G. T. (2010). Regulatory T cells induced by Mycobacterium chelonae sensitization influence murine responses to bacille Calmette-Guerin. J. Leukoc. Biol. 88, 1073–1080. doi: 10.1189/jlb.0809582

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Horenstein, A. L., Chillemi, A., Zaccarello, G., Bruzzone, S., Quarona, V., Zito, A.,et al. (2013). A CD38/CD203a/CD73 ectoenzymatic pathway independent of CD39 drives a novel adenosinergic loop in human T lymphocytes. Oncoimmunology 2:e26246. doi: 10.4161/onci.26246

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Hori, S., Nomura, T., and Sakaguchi, S. (2003). Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061. doi: 10.1126/science.1079490

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Hu, D., Ikizawa, K., Lu, L., Sanchirico, M. E., Shinohara, M. L., and Cantor, H. (2004). Analysis of regulatory CD8 T cells in Qa-1-deficient mice. Nat. Immunol. 5, 516–523. doi: 10.1038/ni1063

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Jepsen, M. P., Jogdand, P. S., Singh, S. K., Esen, M., Christiansen, M., Issifou, S.,et al. (2013). The malaria vaccine candidate GMZ2 elicits functional antibodies in individuals from malaria endemic and non-endemic areas. J. Infect. Dis. 208, 479–488. doi: 10.1093/infdis/jit185

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Jones, C., Pollock, L., Barnett, S. M., Battersby, A., and Kampmann, B. (2014). The relationship between concentration of specific antibody at birth and subsequent response to primary immunization. Vaccine 32, 996–1002. doi: 10.1016/j.vaccine.2013.11.104

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kaleebu, P., Njai, H. F., Wang, L., Jones, N., Ssewanyana, I., Richardson, P.,et al. (2014). Immunogenicity of ALVAC-HIV vCP1521 in infants of HIV-1-infected women in Uganda (HPTN 027): the first pediatric HIV vaccine trial in Africa. J. Acquir. Immune Defic. Syndr. 65, 268–277. doi: 10.1097/01.qai.0000435600.65845.31

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kanegane, H., Miyawaki, T., Kato, K., Yokoi, T., Uehara, T., Yachie, A.,et al. (1991). A novel subpopulation of CD45RA+ CD4+ T cells expressing IL-2 receptor alpha-chain (CD25) and having a functionally transitional nature into memory cells. Int. Immunol. 3, 1349–1356. doi: 10.1093/intimm/3.12.1349

CrossRef Full Text

Kanra, G., Yalcin, S. S., Ceyhan, M., and Yurdakok, K. (2000). Clinical trial to evaluate immunogenicity and safety of inactivated hepatitis A vaccination starting at 2-month-old children. Turk. J. Pediatr. 42, 105–108.

Pubmed Abstract | Pubmed Full Text

Kao, J. Y., Zhang, M., Miller, M. J., Mills, J. C., Wang, B., Liu, M.,et al. (2010). Helicobacter pylori immune escape is mediated by dendritic cell-induced Treg skewing and Th17 suppression in mice. Gastroenterology 138, 1046–1054. doi: 10.1053/j.gastro.2009.11.043

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kared, H., Fabre, T., Bedard, N., Bruneau, J., and Shoukry, N. H. (2013). Galectin-9 and IL-21 mediate cross-regulation between Th17 and Treg cells during acute hepatitis C. PLoS Pathog. 9:e1003422. doi: 10.1371/journal.ppat.1003422

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Keenan, B. P., Saenger, Y., Kafrouni, M. I., Leubner, A., Lauer, P., Maitra, A.,et al. (2014). A Listeria vaccine and depletion of T-regulatory cells activate immunity against early stage pancreatic intraepithelial neoplasms and prolong survival of mice. Gastroenterology 146, 1784.e6–1794.e6. doi: 10.1053/j.gastro.2014.02.055

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Klages, K., Mayer, C. T., Lahl, K., Loddenkemper, C., Teng, M. W., Ngiow, S. F.,et al. (2010). Selective depletion of Foxp3+ regulatory T cells improves effective therapeutic vaccination against established melanoma. Cancer Res. 70, 7788–7799. doi: 10.1158/0008-5472.CAN-10-1736

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kohm, A. P., Mcmahon, J. S., Podojil, J. R., Begolka, W. S., Degutes, M., Kasprowicz, D. J.,et al. (2006). Cutting Edge: Anti-CD25 monoclonal antibody injection results in the functional inactivation, not depletion, of CD4+CD25+ T regulatory cells. J. Immunol. 176, 3301–3305. doi: 10.4049/jimmunol.176.6.3301

CrossRef Full Text

Kollmann, T. R., Crabtree, J., Rein-Weston, A., Blimkie, D., Thommai, F., Wang, X. Y.,et al. (2009). Neonatal innate TLR-mediated responses are distinct from those of adults. J. Immunol. 183, 7150–7160. doi: 10.4049/jimmunol.0901481

CrossRef Full Text

Kollmann, T. R., Levy, O., Montgomery, R. R., and Goriely, S. (2012). Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly. Immunity 37, 771–783. doi: 10.1016/j.immuni.2012.10.014

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Koukouikila-Koussounda, F., Ntoumi, F., Ndounga, M., Tong, H. V., Abena, A. A., and Velavan, T. P. (2013). Genetic evidence of regulatory gene variants of the STAT6, IL10R and FOXP3 locus as a susceptibility factor in uncomplicated malaria and parasitaemia in Congolese children. Malar. J. 12:9. doi: 10.1186/1475-2875-12-9

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Kruetzmann, S., Rosado, M. M., Weber, H., Germing, U., Tournilhac, O., Peter, H. H.,et al. (2003). Human immunoglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen. J. Exp. Med. 197, 939–945. doi: 10.1084/jem.20022020

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lacan, G., Dang, H., Middleton, B., Horwitz, M. A., Tian, J., Melega, W. P.,et al. (2013). Bacillus Calmette-Guerin vaccine-mediated neuroprotection is associated with regulatory T-cell induction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. J. Neurosci. Res. 91, 1292–1302. doi: 10.1002/jnr.23253

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lahl, K., and Sparwasser, T. (2011). In vivo depletion of FoxP3+ Tregs using the DEREG mouse model. Methods Mol. Biol. 707, 157–172. doi: 10.1007/978-1-61737-979-6_10

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Langrish, C. L., Buddle, J. C., Thrasher, A. J., and Goldblatt, D. (2002). Neonatal dendritic cells are intrinsically biased against Th-1 immune responses. Clin. Exp. Immunol. 128, 118–123. doi: 10.1046/j.1365-2249.2002.01817.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Laurens, M. B., Thera, M. A., Coulibaly, D., Ouattara, A., Kone, A. K., Guindo, A. B.,et al. (2013). Extended safety, immunogenicity and efficacy of a blood-stage malaria vaccine in Malian children: 24-month follow-up of a randomized, double-blinded phase 2 trial. PLoS ONE 8:e79323. doi: 10.1371/journal.pone.0079323

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Le, D. T., and Jaffee, E. M. (2012). Regulatory T-cell modulation using cyclophosphamide in vaccine approaches: a current perspective. Cancer Res. 72, 3439–3444. doi: 10.1158/0008-5472.CAN-11-3912

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Levings, M. K., and Roncarolo, M. G. (2000). T-regulatory 1 cells: a novel subset of CD4 T cells with immunoregulatory properties. J. Allergy Clin. Immunol. 106, S109–S112. doi: 10.1067/mai.2000.106635

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Levy, O. (2007). Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat. Rev. Immunol. 7, 379–390. doi: 10.1038/nri2075

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Levy, O., Coughlin, M., Cronstein, B. N., Roy, R. M., Desai, A., and Wessels, M. R. (2006). The adenosine system selectively inhibits TLR-mediated TNF-alpha production in the human newborn. J. Immunol. 177, 1956–1966. doi: 10.4049/jimmunol.177.3.1956

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Levy, O., and Wynn, J. L. (2014). A prime time for trained immunity: innate immune memory in newborns and infants. Neonatology 105, 136–141. doi: 10.1159/000356035

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lin, S. J., Lu, C. H., Yan, D. C., Lee, P. T., Hsiao, H. S., and Kuo, M. L. (2014). Expansion of regulatory T cells from umbilical cord blood and adult peripheral blood CD4CD25 T cells. Immunol. Res. doi: 10.1007/s12026-014-8488-1 [Epub ahead of print].

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Liu, W., Putnam, A. L., Xu-Yu, Z., Szot, G. L., Lee, M. R., Zhu, S.,et al. (2006). CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J. Exp. Med. 203, 1701–1711. doi: 10.1084/jem.20060772

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Liu, Y., Lan, Q., Lu, L., Chen, M., Xia, Z., Ma, J.,et al. (2014). Phenotypic and functional characteristic of a newly identified CD8+ Foxp3- CD103+ regulatory T cells. J. Mol. Cell Biol. 6, 81–92. doi: 10.1093/jmcb/mjt026

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lu, L., Kim, H. J., Werneck, M. B., and Cantor, H. (2008). Regulation of CD8+ regulatory T cells: Interruption of the NKG2A-Qa-1 interaction allows robust suppressive activity and resolution of autoimmune disease. Proc. Natl. Acad. Sci. U.S.A. 105, 19420–19425. doi: 10.1073/pnas.0810383105

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Lu, W., Chen, S., Lai, C., Guo, W., Fu, L., and Andrieu, J. M. (2012). Induction of CD8+ regulatory T cells protects macaques against SIV challenge. Cell Rep. 2, 1736–1746. doi: 10.1016/j.celrep.2012.11.016

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Luciano, A. A., Arbona-Ramirez, I. M., Ruiz, R., Llorens-Bonilla, B. J., Martinez-Lopez, D. G., Funderburg, N.,et al. (2014). Alterations in regulatory T cell subpopulations seen in preterm infants. PLoS ONE 9:e95867. doi: 10.1371/journal.pone.0095867

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ly, N. P., Ruiz-Perez, B., Mcloughlin, R. M., Visness, C. M., Wallace, P. K., Cruikshank, W. W.,et al. (2009). Characterization of regulatory T cells in urban newborns. Clin. Mol. Allergy 7:8. doi: 10.1186/1476-7961-7-8

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Macatangay, B. J., Szajnik, M. E., Whiteside, T. L., Riddler, S. A., and Rinaldo, C. R. (2010). Regulatory T cell suppression of Gag-specific CD8 T cell polyfunctional response after therapeutic vaccination of HIV-1-infected patients on ART. PLoS ONE 5:e9852. doi: 10.1371/journal.pone.0009852

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Macdonald, A. J., Duffy, M., Brady, M. T., Mckiernan, S., Hall, W., Hegarty, J.,et al. (2002). CD4 T helper type 1 and regulatory T cells induced against the same epitopes on the core protein in hepatitis C virus-infected persons. J. Infect. Dis. 185, 720–727. doi: 10.1086/339340

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Mandapathil, M., Hilldorfer, B., Szczepanski, M. J., Czystowska, M., Szajnik, M., Ren, J.,et al. (2010). Generation and accumulation of immunosuppressive adenosine by human CD4+CD25highFOXP3+ regulatory T cells. J. Biol. Chem. 285, 7176–7186. doi: 10.1074/jbc.M109.047423

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Marchant, A., Goetghebuer, T., Ota, M. O., Wolfe, I., Ceesay, S. J., De Groote, D.,et al. (1999). Newborns develop a Th1-type immune response to Mycobacterium bovis Bacillus Calmette-Guerin vaccination. J. Immunol. 163, 2249–2255.

Pubmed Abstract | Pubmed Full Text

Mattarollo, S. R., Steegh, K., Li, M., Duret, H., Foong Ngiow, S., and Smyth, M. J. (2013). Transient Foxp3(+) regulatory T-cell depletion enhances therapeutic anticancer vaccination targeting the immune-stimulatory properties of NKT cells. Immunol. Cell Biol. 91, 105–114. doi: 10.1038/icb.2012.58

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Mayer, C. T., Floess, S., Baru, A. M., Lahl, K., Huehn, J., and Sparwasser, T. (2011). CD8+ Foxp3+ T cells share developmental and phenotypic features with classical CD4+ Foxp3+ regulatory T cells but lack potent suppressive activity. Eur. J. Immunol. 41, 716–725. doi: 10.1002/eji.201040913

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Mayer, E., Bannert, C., Gruber, S., Klunker, S., Spittler, A., Akdis, C. A.,et al. (2012). Cord blood derived CD4+ CD25(high) T cells become functional regulatory T cells upon antigen encounter. PLoS ONE 7:e29355. doi: 10.1371/journal.pone.0029355

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Mills, K. H., and Mcguirk, P. (2004). Antigen-specific regulatory T cells – their induction and role in infection. Semin. Immunol. 16, 107–117. doi: 10.1016/j.smim.2003.12.006

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Minigo, G., Woodberry, T., Piera, K. A., Salwati, E., Tjitra, E., Kenangalem, E.,et al. (2009). Parasite-dependent expansion of TNF receptor II-positive regulatory T cells with enhanced suppressive activity in adults with severe malaria. PLoS Pathog. 5:e1000402. doi: 10.1371/journal.ppat.1000402

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Mitchell, D. A., Cui, X., Schmittling, R. J., Sanchez-Perez, L., Snyder, D. J., Congdon, K. L.,et al. (2011). Monoclonal antibody blockade of IL-2 receptor alpha during lymphopenia selectively depletes regulatory T cells in mice and humans. Blood 118, 3003–3012. doi: 10.1182/blood-2011-02-334565

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Miyara, M., Yoshioka, Y., Kitoh, A., Shima, T., Wing, K., Niwa, A.,et al. (2009). Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30, 899–911. doi: 10.1016/j.immuni.2009.03.019

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Moore, A. C., Gallimore, A., Draper, S. J., Watkins, K. R., Gilbert, S. C., and Hill, A. V. (2005). Anti-CD25 antibody enhancement of vaccine-induced immunogenicity: increased durable cellular immunity with reduced immunodominance. J. Immunol. 175, 7264–7273. doi: 10.4049/jimmunol.175.11.7264

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Moorman, J. P., Wang, J. M., Zhang, Y., Ji, X. J., Ma, C. J., Wu, X. Y.,et al. (2012). Tim-3 pathway controls regulatory and effector T cell balance during hepatitis C virus infection. J. Immunol. 189, 755–766. doi: 10.4049/jimmunol.1200162

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Mwacharo, J., Dunachie, S. J., Kai, O., Hill, A. V., Bejon, P., and Fletcher, H. A. (2009). Quantitative PCR evaluation of cellular immune responses in Kenyan children vaccinated with a candidate malaria vaccine. PLoS ONE 4:e8434. doi: 10.1371/journal.pone.0008434

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Nettenstrom, L., Alderson, K., Raschke, E. E., Evans, M. D., Sondel, P. M., Olek, S.,et al. (2013). An optimized multi-parameter flow cytometry protocol for human T regulatory cell analysis on fresh and viably frozen cells, correlation with epigenetic analysis, and comparison of cord and adult blood. J. Immunol. Methods 387, 81–88. doi: 10.1016/j.jim.2012.09.014

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ngamphaiboon, J., Theamboonlert, A., and Poovorawan, Y. (1998). Serum IgG subclass levels in a group of healthy Thai children. Asian Pac. J. Allergy Immunol. 16, 49–55.

Pubmed Abstract | Pubmed Full Text

Nguyen, M., Leuridan, E., Zhang, T., De Wit, D., Willems, F., Van Damme, P.,et al. (2010). Acquisition of adult-like TLR4 and TLR9 responses during the first year of life. PLoS ONE 5:e10407. doi: 10.1371/journal.pone.0010407

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Ogwang, C., Afolabi, M., Kimani, D., Jagne, Y. J., Sheehy, S. H., Bliss, C. M.,et al. (2013). Safety and immunogenicity of heterologous prime-boost immunisation with Plasmodium falciparum malaria candidate vaccines, ChAd63 ME-TRAP and MVA ME-TRAP, in healthy Gambian and Kenyan adults. PLoS ONE 8:e57726. doi: 10.1371/journal.pone.0057726

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Olotu, A., Fegan, G., Wambua, J., Nyangweso, G., Awuondo, K. O., Leach, A.,et al. (2013). Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure. N. Engl. J. Med. 368, 1111–1120. doi: 10.1056/NEJMoa1207564

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Olotu, A., Lusingu, J., Leach, A., Lievens, M., Vekemans, J., Msham, S.,et al. (2011). Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania: a randomised controlled trial. Lancet Infect. Dis. 11, 102–109. doi: 10.1016/S1473-3099(10)70262-0

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Patton, D. T., Wilson, M. D., Rowan, W. C., Soond, D. R., and Okkenhaug, K. (2011). The PI3K p110delta regulates expression of CD38 on regulatory T cells. PLoS ONE 6:e17359. doi: 10.1371/journal.pone.0017359

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Peggs, K. S., Quezada, S. A., Chambers, C. A., Korman, A. J., and Allison, J. P. (2009). Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J. Exp. Med. 206, 1717–1725. doi: 10.1084/jem.20082492

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Perez-Machado, M. A., Ashwood, P., Thomson, M. A., Latcham, F., Sim, R., Walker-Smith, J. A.,et al. (2003). Reduced transforming growth factor-beta1-producing T cells in the duodenal mucosa of children with food allergy. Eur. J. Immunol. 33, 2307–2315. doi: 10.1002/eji.200323308

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Perret, R., Sierro, S. R., Botelho, N. K., Corgnac, S., Donda, A., and Romero, P. (2013). Adjuvants that improve the ratio of antigen-specific effector to regulatory T cells enhance tumor immunity. Cancer Res. 73, 6597–6608. doi: 10.1158/0008-5472.CAN-13-0875

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Philbin, V. J., Dowling, D. J., Gallington, L. C., Cortes, G., Tan, Z., Suter, E. E.,et al. (2012). Imidazoquinoline Toll-like receptor 8 agonists activate human newborn monocytes and dendritic cells through adenosine-refractory and caspase-1-dependent pathways. J. Allergy Clin. Immunol. 130, 195.e9–204.e9. doi: 10.1016/j.jaci.2012.02.042

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Philbin, V. J., and Levy, O. (2009). Developmental biology of the innate immune response: implications for neonatal and infant vaccine development. Pediatr. Res. 65, 98R–105R. doi: 10.1203/PDR.0b013e31819f195d

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Power Coombs, M. R., Belderbos, M. E., Gallington, L. C., Bont, L., and Levy, O. (2011). Adenosine modulates Toll-like receptor function: basic mechanisms and translational opportunities. Expert Rev. Anti Infect. Ther. 9, 261–269. doi: 10.1586/eri.10.158

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Raskovalova, T., Huang, X., Sitkovsky, M., Zacharia, L. C., Jackson, E. K., and Gorelik, E. (2005). Gs protein-coupled adenosine receptor signaling and lytic function of activated NK cells. J. Immunol. 175, 4383–4391. doi: 10.4049/jimmunol.175.7.4383

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Rech, A. J., Mick, R., Martin, S., Recio, A., Aqui, N. A., Powell, D. J.,et al. (2012). CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci. Transl. Med. 4:134ra62.

Rech, A. J., and Vonderheide, R. H. (2009). Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells. Ann. N. Y. Acad. Sci. 1174, 99–106. doi: 10.1111/j.1749-6632.2009.04939.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Roncarolo, M. G., Gregori, S., Battaglia, M., Bacchetta, R., Fleischhauer, K., and Levings, M. K. (2006). Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol. Rev. 212, 28–50. doi: 10.1111/j.0105-2896.2006.00420.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Rts, S. C. T. P., Agnandji, S. T., Lell, B., Fernandes, J. F., Abossolo, B. P., Methogo, B. G.,et al. (2012). A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N. Engl. J. Med. 367, 2284–2295. doi: 10.1056/NEJMoa1208394

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Saison, J., Ferry, T., Demaret, J., Maucort Boulch, D., Venet, F., Perpoint, T.,et al. (2014). Association between discordant immunological response to highly active anti-retroviral therapy, regulatory T cell percentage, immune cell activation and very low-level viraemia in HIV-infected patients. Clin. Exp. Immunol. 176, 401–409. doi: 10.1111/cei.12278

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sakaguchi, S. (2000). Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101, 455–458. doi: 10.1016/S0092-8674(00)80856-9

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M., and Toda, M. (1995). Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164.

Sallusto, F., Lenig, D., Forster, R., Lipp, M., and Lanzavecchia, A. (1999). Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712. doi: 10.1038/44385

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sansom, D. M., and Walker, L. S. (2006). The role of CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) in regulatory T-cell biology. Immunol. Rev. 212, 131–148. doi: 10.1111/j.0105-2896.2006.00419.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Santner-Nanan, B., Seddiki, N., Zhu, E., Quent, V., Kelleher, A., Fazekas De St Groth, B.,et al. (2008). Accelerated age-dependent transition of human regulatory T cells to effector memory phenotype. Int. Immunol. 20, 375–383. doi: 10.1093/intimm/dxm151

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Scalzo-Inguanti, K., and Plebanski, M. (2011). CD38 identifies a hypo-proliferative IL-13-secreting CD4+ T-cell subset that does not fit into existing naive and memory phenotype paradigms. Eur. J. Immunol. 41, 1298–1308. doi: 10.1002/eji.201040726

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Schmetterer, K. G., Neunkirchner, A., and Pickl, W. F. (2012). Naturally occurring regulatory T cells: markers, mechanisms, and manipulation. FASEB J. 26, 2253–2276. doi: 10.1096/fj.11-193672

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Scholzen, A., Minigo, G., and Plebanski, M. (2010). Heroes or villains? T regulatory cells in malaria infection. Trends Parasitol. 26, 16–25. doi: 10.1016/j.pt.2009.10.004

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Scholzen, A., Mittag, D., Rogerson, S. J., Cooke, B. M., and Plebanski, M. (2009). Plasmodium falciparum-mediated induction of human CD25Foxp3 CD4 T cells is independent of direct TCR stimulation and requires IL-2, IL-10 and TGFbeta. PLoS Pathog. 5:e1000543. doi: 10.1371/journal.ppat.1000543

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Seddiki, N., Santner-Nanan, B., Martinson, J., Zaunders, J., Sasson, S., Landay, A.,et al. (2006). Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J. Exp. Med. 203, 1693–1700. doi: 10.1084/jem.20060468

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Serana, F., Chiarini, M., Quiros-Roldan, E., Gotti, D., Zanotti, C., Sottini, A.,et al. (2014). Modulation of regulatory T-cell subsets in very long-term treated aviremic HIV(+) patients and untreated viremic patients. Open AIDS J. 8, 1–6. doi: 10.2174/1874613601408010001

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Siegrist, C. A. (2003). Mechanisms by which maternal antibodies influence infant vaccine responses: review of hypotheses and definition of main determinants. Vaccine 21, 3406–3412. doi: 10.1016/S0264-410X(03)00342-6

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Siegrist, C. A., Barrios, C., Martinez, X., Brandt, C., Berney, M., Cordova, M.,et al. (1998). Influence of maternal antibodies on vaccine responses: inhibition of antibody but not T cell responses allows successful early prime-boost strategies in mice. Eur. J. Immunol. 28, 4138–4148. doi: 10.1002/(SICI)1521-4141(199812)28:12<4138::AID-IMMU4138>3.0.CO;2-L

CrossRef Full Text

Simone, R., Zicca, A., and Saverino, D. (2008). The frequency of regulatory CD3+CD8+CD28- CD25+ T lymphocytes in human peripheral blood increases with age. J. Leukoc. Biol. 84, 1454–1461. doi: 10.1189/jlb.0907627

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Sitkovsky, M. V., and Ohta, A. (2005). The ‘danger’ sensors that STOP the immune response: the A2 adenosine receptors? Trends Immunol. 26, 299–304. doi: 10.1016/j.it.2005.04.004

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Smith, T. R., and Kumar, V. (2008). Revival of CD8+ Treg-mediated suppression. Trends Immunol. 29, 337–342. doi: 10.1016/j.it.2008.04.002

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Suzuki, M., Jagger, A. L., Konya, C., Shimojima, Y., Pryshchep, S., Goronzy, J. J.,et al. (2012). CD8+CD45RA+CCR7+FOXP3+ T cells with immunosuppressive properties: a novel subset of inducible human regulatory T cells. J. Immunol. 189, 2118–2130. doi: 10.4049/jimmunol.1200122

CrossRef Full Text

Suzuki, M., Konya, C., Goronzy, J. J., and Weyand, C. M. (2008). Inhibitory CD8+ T cells in autoimmune disease. Hum. Immunol. 69, 781–789. doi: 10.1016/j.humimm.2008.08.283

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Takahata, Y., Nomura, A., Takada, H., Ohga, S., Furuno, K., Hikino, S.,et al. (2004). CD25+CD4+ T cells in human cord blood: an immunoregulatory subset with naive phenotype and specific expression of forkhead box p3 (Foxp3) gene. Exp. Hematol. 32, 622–629. doi: 10.1016/j.exphem.2004.03.012

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Tan, C., Reddy, V., Dannull, J., Ding, E., Nair, S. K., Tyler, D. S.,et al. (2013). Impact of anti-CD25 monoclonal antibody on dendritic cell-tumor fusion vaccine efficacy in a murine melanoma model. J. Transl. Med. 11:148. doi: 10.1186/1479-5876-11-148

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Todryk, S. M., Bejon, P., Mwangi, T., Plebanski, M., Urban, B., Marsh, K.,et al. (2008). Correlation of memory T cell responses against TRAP with protection from clinical malaria, and CD4 CD25 high T cells with susceptibility in Kenyans. PLoS ONE 3:e2027. doi: 10.1371/journal.pone.0002027

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Tosello, V., Odunsi, K., Souleimanian, N. E., Lele, S., Shrikant, P., Old, L. J.,et al. (2008). Differential expression of CCR7 defines two distinct subsets of human memory CD4+CD25+ Tregs. Clin. Immunol. 126, 291–302. doi: 10.1016/j.clim.2007.11.008

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Uss, E., Rowshani, A. T., Hooibrink, B., Lardy, N. M., Van Lier, R. A., and Ten Berge, I. J. (2006). CD103 is a marker for alloantigen-induced regulatory CD8+ T cells. J. Immunol. 177, 2775–2783. doi: 10.4049/jimmunol.177.5.2775

CrossRef Full Text

Vieira, P. L., Christensen, J. R., Minaee, S., O’Neill, E. J., Barrat, F. J., Boonstra, A.,et al. (2004). IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J. Immunol. 172, 5986–5993. doi: 10.4049/jimmunol.172.10.5986

CrossRef Full Text

Voo, K. S., Bover, L., Harline, M. L., Vien, L. T., Facchinetti, V., Arima, K.,et al. (2013). Antibodies targeting human OX40 expand effector T cells and block inducible and natural regulatory T cell function. J. Immunol. 191, 3641–3650. doi: 10.4049/jimmunol.1202752

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Walker, L. S. (2013). Treg and CTLA-4: two intertwining pathways to immune tolerance. J. Autoimmun. 45, 49–57. doi: 10.1016/j.jaut.2013.06.006

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Walther, B., Miles, D. J., Waight, P., Palmero, M. S., Ojuola, O., Touray, E. S.,et al. (2012). Placental malaria is associated with attenuated CD4 T-cell responses to tuberculin PPD 12 months after BCG vaccination. BMC Infect. Dis. 12:6. doi: 10.1186/1471-2334-12-6

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Walther, M., Jeffries, D., Finney, O. C., Njie, M., Ebonyi, A., Deininger, S.,et al. (2009). Distinct roles for FOXP3 and FOXP3 CD4 T cells in regulating cellular immunity to uncomplicated and severe Plasmodium falciparum malaria. PLoS Pathog. 5:e1000364. doi: 10.1371/journal.ppat.1000364

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Walther, M., Tongren, J. E., Andrews, L., Korbel, D., King, E., Fletcher, H.,et al. (2005). Upregulation of TGF-beta, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection. Immunity 23, 287–296. doi: 10.1016/j.immuni.2005.08.006

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wammes, L. J., Wiria, A. E., Toenhake, C. G., Hamid, F., Liu, K. Y., Suryani, H.,et al. (2013). Asymptomatic plasmodial infection is associated with increased tumor necrosis factor receptor II-expressing regulatory T cells and suppressed type 2 immune responses. J. Infect. Dis. 207, 1590–1599. doi: 10.1093/infdis/jit058

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wang, W. H., Ming, L., Wang, Y., Kan, Q. C., and Zhang, X. Y. (2013). High frequency of regulatory T cells among HIV type 1-infected men who have sex with men correlates with disease progression. Chin. Med. J. (Engl.) 126, 2054–2061.

Pubmed Abstract | Pubmed Full Text

Wing, J. B., and Sakaguchi, S. (2012). Multiple Treg suppressive modules and their adaptability. Front. Immunol. 3:178. doi: 10.3389/fimmu.2012.00178

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wing, K., Ekmark, A., Karlsson, H., Rudin, A., and Suri-Payer, E. (2002). Characterization of human CD25+ CD4+ T cells in thymus, cord and adult blood. Immunology 106, 190–199. doi: 10.1046/j.1365-2567.2002.01412.x

CrossRef Full Text

Wing, K., Larsson, P., Sandstrom, K., Lundin, S. B., Suri-Payer, E., and Rudin, A. (2005). CD4+ CD25+ FOXP3+ regulatory T cells from human thymus and cord blood suppress antigen-specific T cell responses. Immunology 115, 516–525. doi: 10.1111/j.1365-2567.2005.02186.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wing, K., Yamaguchi, T., and Sakaguchi, S. (2011). Cell-autonomous and -non-autonomous roles of CTLA-4 in immune regulation. Trends Immunol. 32, 428–433. doi: 10.1016/j.it.2011.06.002

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Wu, J. J., Chen, G., Liu, J., Wang, T., Zheng, W., and Cao, Y. M. (2010). Natural regulatory T cells mediate the development of cerebral malaria by modifying the pro-inflammatory response. Parasitol. Int. 59, 232–241. doi: 10.1016/j.parint.2010.02.007

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Yeung, L. T., King, S. M., and Roberts, E. A. (2001). Mother-to-infant transmission of hepatitis C virus. Hepatology 34, 223–229. doi: 10.1053/jhep.2001.25885

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Zandvoort, A., and Timens, W. (2002). The dual function of the splenic marginal zone: essential for initiation of anti-TI-2 responses but also vital in the general first-line defense against blood-borne antigens. Clin. Exp. Immunol. 130, 4–11. doi: 10.1046/j.1365-2249.2002.01953.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Keywords: regulatory T cells, vaccines, infants, neonates, immunogenicity, immune modulation, adjuvants

Citation: Ndure J and Flanagan KL (2014) Targeting regulatory T cells to improve vaccine immunogenicity in early life. Front. Microbiol. 5:477. doi: 10.3389/fmicb.2014.00477

Received: 06 June 2014; Accepted: 25 August 2014;
Published online: 11 September 2014.

Edited by:

Shuo Li, Burnet Institute, Australia

Reviewed by:

Diego A. Vargas-Inchaustegui, National Cancer Institute, USA
Lenny Moise, EpiVax, USA

Copyright © 2014 Ndure and Flanagan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Katie L. Flanagan, Vaccine and Infectious Diseases Laboratory, Department of Immunology, Monash University, Level 2, AMREP Building, 89 Commercial Road, Melbourne, VIC 3004, Australia e-mail: katie.flanagan@dhhs.tas.gov.au

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.