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Review ARTICLE

Front. Immunol., 14 August 2014 | https://doi.org/10.3389/fimmu.2014.00390

NK cell subset redistribution during the course of viral infections

imageEnrico Lugli1†, imageEmanuela Marcenaro2† and imageDomenico Mavilio1,2,3*
  • 1Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Milan, Italy
  • 2Dipartimento di Medicina Sperimentale, Centro di Eccellenza per le Ricerche Biomediche, Università degli Studi di Genova, Genova, Italy
  • 3Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy

Natural killer (NK) cells are important effectors of innate immunity that play a critical role in the control of human viral infections. Indeed, given their capability to directly recognize virally infected cells without the need of specific antigen presentation, NK cells are on the first line of defense against these invading pathogens. By establishing cellular networks with a variety of cell types such as dendritic cells, NK cells can also amplify anti-viral adaptive immune responses. In turn, viruses evolved and developed several mechanisms to evade NK cell-mediated immune activity. It has been reported that certain viral diseases, including human immunodeficiency virus-1 as well as human cytomegalovirus infections, are associated with a pathologic redistribution of NK cell subsets in the peripheral blood. In particular, it has been observed the expansion of unconventional CD56neg NK cells, whose effector functions are significantly impaired as compared to that of conventional CD56pos NK cells. In this review, we address the impact of these two chronic viral infections on the functional and phenotypic perturbations of human NK cell compartment.

Introduction

In the absence of drugs that are able to eradicate and cure viral infections, the presence of efficient immune responses is key in the control and clearance of virally infected cells. Natural killer (NK) cells represent the first line of defense against viral infections, as it became clear since the first experimental evidence in the late 1980s reporting severe and recurrent herpes virus infections in a young patient with NK cell deficiency (1). The fact that NK cells do not need a prior antigen sensitization makes them ready to fight against pathogens starting from the early phases of innate immune responses through several effector functions controlled by a dynamic balance between inhibitory and activating NK cell receptors (NKRs) (2). Indeed, NK cells are able to lyse “non-self” cellular targets while sparing normal cells that express adequate levels of “self” major histocompatibility complex of class I (MHC-I) molecules. This cytolytic function is regulated by a heterogeneous family of inhibitory NKRs (iNKRs) that bind specifically to either classical or non-classical human leukocyte antigen (HLA) alleles (3). Diminution or absence of expression of HLA-I molecules on the surface of virally infected cells results in reduced engagement of iNKRs which, in turn, allow a large group of activating NKRs (aNKRs) to trigger cytotoxicity. The “on signal” exerted by aNKRs to trigger NK cell killing depends on the induced expression of putative ligands for activating receptors on virally infected target cells. The recognition of these specific ligands is required for the engagement of aNKR-mediated downstream pathways associated with the NK cell release of lytic granules (413).

Upon activation, NK cells also produce several chemokines such as CCL3/MIP1α, CCL4/MIP1β CCL5/RANTES, and cytokines such as interferon-γ (IFN-γ), tumor necrosis factor (TNF), and granulocyte/macrophage colony-stimulating factor (GM-CSF). These soluble factors play not only an important regulatory role in hematopoiesis and cellular activation, but are also involved in the suppression of human immunodeficiency virus-1 (HIV-1) replication through non-cytolytic mechanisms (2, 10, 1417). NK cells are also endowed with the ability of either priming or taking part to cellular networks of interactions. In fact, it has been shown that NK cells are engaged in an active and bi-directional cross talk with autologous dendritic cells (DCs) through a process that requires both NK cell–DC cellular interactions and secretion of specific cytokines (1825). Furthermore, monocytes/macrophages and neutrophils have been shown to regulate the recruitment and the activation of NK cells, which, in turn, can eliminate over-stimulated macrophages (2629). It has been also reported that human neutrophils are able to establish a network with both NK cells and 6-sulfo LacNAc+ DCs (slanDC). This “mènage à trois” involves direct reciprocal interactions as well as positive amplification loops mediated by cell-derived cytokines with the aim of inducing IFN-γ production by NK cells (30). The final outcome of these synergic NK cell interactions is the coordination and optimization of both innate and adaptive immunity in response to inflammatory stimuli such as viral infections at tissue sites (31).

Under physiological conditions, the distribution of the surface markers CD56 and CD16 (FcγRIII) defines two subsets of CD14neg/CD3neg/CD19neg NK lymphocytes: the CD56bright/CD16neg-dim (CD56bright) population that accounts for ~10% of blood NK cells and the CD56dim/CD16bright (CD56dim) cells that comprise for ~90% of circulating NK cells (17, 32). CD56bright NK cells exert only marginal cytotoxic capacity and yet produce high amounts of cytokines like IFN-γ, TNF, and GM-CSF. Their degree of proliferation in response to activation stimuli is much higher as compared to that of CD56dim NK cells. Given the pleiotropic roles of the cytokines on multiple immune and non-immune populations, CD56bright NK cells have been generally referred to as regulatory NK cells. Conversely, CD56dim NK cells were originally identified as the main subset endowed with cytotoxic capacity, although subsequent works indicated that they can also produce relatively high amounts of pro-inflammatory cytokines following the engagement of aNKRs (3236). The different functional outcomes of CD56bright and CD56dim NK cells are associated with different repertoires of NKRs and with distinct homing capacities that are determined at the level of chemokine receptor expression on the cell surface. Indeed, CD56dim NK cells preferentially migrate to inflamed peripheral tissues on the basis of their increased expression of CXCR1, CX3CR1, and ChemR23, while the CD56bright subset expressing CCR7 preferentially homes to secondary lymphoid organs (3739). Remarkably, recent data indicate that, in several pathological conditions including viral infections, CD56dim NK cells may also express CCR7 de novo and migrate toward lymph nodes (4042).

It is well known that viruses remarkably affect NK cell homeostasis, phenotype, and functions, thus highlighting the key roles played by NK lymphocytes in the physiopathology of chronic and inflammatory viral disorders. This review provides an updated summary of the virally induced changes of NK cell phenotype and functions and of their implications in NK cell physiology and physiopathology.

NK Cell Responses to HIV-1

High Frequencies of CD56neg NK Cell Subset in HIV-1 Infection

Although the NK cell population is mainly composed by the two CD56bright and CD56dim subsets, low frequencies of a CD14neg/CD3neg/CD19neg/CD56neg/CD16bright (CD56neg) population are also detected in healthy donors (16, 43). This unusual and rare population has been substantially ignored until mid 1990s, when it has been described that the decrement of absolute numbers of circulating NK cells during the course of HIV-1 infection is associated with expansion of an unconventional subset of CD56neg NK lymphocytes (44). This report opened a new research topic in the field of NK cell biology and many groups, including ours, highlighted the great importance of CD56neg NK cell in the physiopathology of HIV-1 infection. It then became evident that NK cells are remarkably affected by the deleterious effect of ongoing HIV-1 replication. Although NK cells are not productively infected by HIV-1, high and chronic levels of viremia significantly impair NK cell-mediated host immune responses, thus leading to a defective control of viral spreading and, subsequently, to disease progression. This is due, at least in part, to the defective capacities of NK cells from viremic HIV-1-infected patients to eliminate autologous HIV-1-infected CD4pos T cells. Moreover, NK cells from the same individuals displayed impaired killing of cell targets either tumor-transformed or infected by opportunistic pathogens as well as weaker production of anti-viral cytokines/chemokines and defective interactions with autologous DCs (10, 17). In turn, dysfunctions in NK-DC crosstalk impair the maturation of DCs that, instead of priming an effective adaptive immune response by presenting HIV-1 antigens to T cells, contribute to disseminate the infection in secondary lymphoid organs (23). These NK cell aberrancies are a direct consequence of the HIV-1-driven expansion of the highly anergic CD56neg NK cell subset. In patients with chronic or late stage HIV-1 infection and high viral loads, decreased frequencies of CD56dim/CD16pos NK cell populations are counterbalanced by increased percentages of these dysfunctional CD56neg cells expressing an aberrant repertoire of inhibitory and aNKRs. This experimental evidence clarified that, rather than an absolute decrement of total circulating NK cells (44), HIV-1 viremia is associated with a significant and pathological redistribution of NK cell subsets associated with impaired anti-viral responses (12, 16, 23, 4553). The sequential deregulation of NK cell subset has been reported to start from the early phases of HIV-1 infection due to the presence of surface markers highly sensitive to viral replication (33, 53). In particular, it has been reported that the c-lectin-type molecule Siglec-7 (also known as p75/AIRM1), an inhibitory receptor constitutively expressed on all NK cells, is the first marker to be down-regulated during the early phases of HIV-1 infection before the loss of CD56. Siglec-7 down-modulation is preserved throughout the course of the infection and depends on the level of viral replication. Indeed, the small cohort of individuals that do not progress toward AIDS (i.e., the long-term non-progressors) and who naturally display low or undetectable HIV-1 viremia keep a normal distribution of NK cell subsets as identified by the expression of Siglec-7 and CD56. Since all these NK cell phenotypic and functional abnormalities are reversible following a successfully suppression of viral replication, the pathological redistribution of NK cell subsets can also be used to monitor the effectiveness of antiretroviral therapy (ART) (17).

Finally, we recently reported that the NK cell modulation of Siglec-7 in HIV-1 infection is directly involved in HIV-1 pathogenesis (54). In fact, chronic high levels of viral replication lead to a decreased surface expression of Siglec-7 on NK cells counterbalanced by increased levels of soluble Siglec-7 detected in the plasma of viremic HIV-1-infected patients. This soluble form of Siglec-7 is able to directly bind the glycoprotein 120 expressed on HIV-1 envelope and facilitates the infection of Siglec-7neg/CD4pos T cells. In contrast, high levels of HIV-1 viremia do not alter the constitutive expression of Siglec-7 in monocytes and macrophages, whose susceptibility to HIV-1 infection is enhanced by the direct interaction between the virus and this lectin-type receptor (33, 54). These data suggest that, similar to other members of Siglec family (5557), both membrane-bound and soluble Siglec-7 greatly increase the susceptibility of CD4pos cell targets expressing CCR5 or CXCR4 to be infected by HIV-I (54).

Origin of the CD56neg NK Cell Subset

Natural killer cells resulted not to be directly infected by HIV-1 (45) and, therefore, it is unlikely that the expansion of CD56neg NK cell is HIV-1 specific. Indeed, although the origin of CD56neg cells is still being debated, it later became clear that high frequencies of this pathological subset are associated with the presence of chronic and systemic inflammation, which is a hallmark of chronic HIV-1 infection (10, 12). Several studies then investigated other human disorders characterized by high levels of systemic immune activation and reported similar increased percentages of circulating CD56neg NK cells. Among these diseases, there are hepatitis C virus (HCV) (58, 59), human cytomegalovirus (HCMV) (60), hantavirus (61), treponema pallidum (62) infections, post-transplant lymphoproliferative malignancies driven by Epstein–Barr virus (EBV), (63) and autoimmune disorders such as myasthenia gravis (64) and dermatomyositis (65). Expansion of CD56neg NK cells has been described both in HCV as well as in HCV–HIV co-infected patients (59). However, the increase of this aberrant subset is much more contained in mono-infection by HCV compared to HCV–HIV co-infection. Therefore, additional studies are required to clarify whether the accumulation of CD56neg NK cells is a hallmark of chronic HCV infection. Finally, a significant proportion of CD56neg cells have also been found in umbilical cord blood and in healthy infants and are characterized by impaired anti-viral activities (6669).

The fact that high frequencies of CD56neg NK cells are found in so many different either pathological or physiological conditions underline that their ontogenesis relies on mechanism(s) associated with activation of the immune system and not with a specific viral infection or inflammatory disorder. Moreover, in all the above-mentioned disorders as well as in umbilical cord blood, CD56neg cells share the same phenotypic and functional features: (i) low expression of natural cytotoxity receptors (NCRs) and Siglec-7; (ii) reduced cytolytic potential; (iii) decreased production of anti-viral cytokines and chemokines. In regard to their ontogeny, it has been first postulated that this “anergic” CD56neg cells could arise from a failure of NK cell development and/or from inadequate cell stimulation. This theory was mainly supported by experimental evidence showing that the incubation in vitro of CD56neg cells with IL-2, IL-12, and IL-15 induces cell proliferation and restores the classical distribution of CD56 and repertoire of NKRs (44, 59, 67). We have to point out though that therapies with anti-viral drugs (in case of HIV-1 and HCV infections) or with immunosuppressants (for myasthenia gravis and dermatomyositis) restored physiological NK cell phenotype and functions (16, 59, 64, 65).

Unfortunately, there are no reports showing that an in vitro setting could reproduce the expansion of CD56neg cells and this hampered our capacity to disclose the mechanistic insights highlighting this phenomenon. Our current knowledge of NK cell ontogenesis states that CD16neg immature NK (iNK) cells expressing low levels of CD56 and NCRs precede CD56bright NK cells in development (43, 70). Although sharing these phenotypic features with iNKT, CD56neg NK cells also express many NK cell-specific receptors that are not found on iNK cells, including KIRs, CD94/NKG2A, NKG2D and CD16 (10, 43). iNK cells produce high amounts of GM-CSF but not other inflammatory cytokines following phorbol myristate acetate (PMA)/ionomycin stimulation, and they are not even able to kill target cells nor to produce cytokines (70). Moreover, iNK cells develop into CD56bright NK cells after stimulation with IL-15, thus suggesting they are precursors of these cells in vivo (70). On the contrary, CD56neg NK cells retain inflammatory cytokine production and killing capacity, albeit at impaired level compared to conventional CD56pos NK cells (10, 17). Finally, CD56neg cells but not iNK cells have been recently shown to express CD57 (71), a marker of terminal cell differentiation (72). Taken together, these experimental findings strongly suggest that CD56neg NK cells do not derive from iNK cells.

An alternative hypothesis proposed that CD56neg NK cells are mature lymphocytes that recently engaged target cells. Under normal circumstances, NK cells are capable of killing multiple target cells, thus resulting in a reduced, but never complete, loss of perforin and granzyme B (73). In HIV-1-infected patients, decreased granzyme B and perforin expression and increased surface expression of CD107a in the absence of ex vivo stimulation suggests that CD56neg NK cells engage target cells in vivo. Authors also argued that this hypothesis is further supported by the increased expression of CD95 on CD56neg cell subset, thus indicating a more pronounced activation compared to their CD56dim cell counterpart (71). However, the down-regulation of CD56 as a consequence of recent activation is still awaiting confirmation by additional studies. Since the transcriptome of CD56neg NK cells has been found to be more similar to myeloid cells than to traditional CD56dim NK cells (74), CD7, a surface protein expressed on thymocytes and mature T cells, has been proposed as an additional informative marker for their identification. In this regard, CD56neg NK cells have been reported to be a mixed population of CD7pos true NK cells and CD7neg myeloid cells present at a low frequency in healthy donors and expanded in HIV-1 viremic subjects (71).

NK Cell Responses to Human Cytomegalovirus

Similar to what it has been observed in humans (1), mice infected with murine cytomegalovirus (MCMV) and depleted of NK cells were unable to control infection and displayed disseminated MCMV in the lungs and in the liver (75). The anti-viral NK cell responses are particularly relevant when viruses exploit mechanisms of immune evasion, leading to the down-regulation of MHC-I molecules and thus escape from the CD8pos T cell-mediated cytolytic activity. Multiple HCMV-derived proteins have been demonstrated to interfere with the transport or the expression of MHC-I on the cell surface (76). On the other hand, HCMV-infected cells up-regulate ligands for the aNKR NKG2D, including MICA, MICB, and UL-16 binding proteins (ULBPs), thereby facilitating NK cell activation (7779). On average, 50–80% of the human population in Western countries is HCMV-infected, but the virus does not harm the health of immune-competent individuals, unless in specific situations such as maternal HCMV reactivation or primary infection during pregnancy. Instead, immune-compromised individuals, such as those infected with HIV-1 or those who received bone marrow transplantation (BMT), are particularly susceptible to CMV reactivation (80). Following BMT, NK cells recover faster than CD8pos T cells (2–3 weeks vs. 4–6 weeks, depending on the type of transplantation) and possibly mediate a first line of protection against viral dissemination (81). Different groups have recently shown that patients experiencing HCMV reactivation following BMT display highly mature KIRpos, NKG2Aneg, NKG2Cpos, and CD57pos NK cells that are not found in uninfected recipients (8284). A similar NK cell phenotype is observed following acute HCMV infection in healthy individuals (72). Interestingly, modification of the NK cell surface phenotype did not change with resolution of the infection (83), thus suggesting a stable imprinting in the NK cell maturation stage. Similar to what it has been observed in HCV and HIV-1 infections (33, 43), HCMV-reactivations in patients undergoing umbilical cord blood transplantation induce the expansion of the CD56neg/CD16pos/Siglec-7neg NK cell subset (60). The expansion of anergic CD56neg NK cells following HCMV reactivation likely occurs when T cell immunity is impaired and supports the hypothesis that HCMV has a role in immune-senescence (85, 86).

Multiple components of the immune system are thus engaged to protect the host from reactivating CMV replication. The sole NK cell response is likely not sufficient in this regard and must act in concert with recovering CMV-specific CD8pos T cells with the support of CMV-specific CD4pos T cells. This is well demonstrated in individuals infected with HIV, where the loss of antigen-specific CD4pos T cells causes increased susceptibility to opportunistic infections, including CMV reactivation (87). These data altogether suggest that NK cells could be exploited together with CD8pos T cells in the therapeutic treatment of CMV reactivation.

HCMV and Memory NK Cells

Studies in mice led to the demonstration that a population of “memory” NK cells develop following acute infection with MCMV. In particular, it has been reported that NK cells expressing the activating Ly49H receptor undergo a clonal-like expansion upon recognition of the MCMV-encoded m157 antigen and generate long-lived memory NK cells (88). Similarly in humans, it has been recently demonstrated that NKG2Cpos NK cells remarkably increase in frequency following HCMV infection or reactivation and can persist for years (60, 72, 8992). Such expanded NKG2Cpos NK cells may exert an efficient anti-viral activity by producing higher amounts of cytokines, in particular IFN-γ, hence suggesting that “memory-like” NK cell responses may occur in humans as well. However, NKG2C cannot be considered as a univocal marker of “memory-like” NK cells. Indeed, recent reports suggest that also other NKRs that are preferentially found in terminally differentiated NK cells, including activating KIRs or CD57, are up-regulated following HCMV reactivation. In this context, a number of recent studies suggest that the presence of activating KIRs correlates with protection against viral infections (84, 93).

Despite “memory-like” NK cells mostly display a CD56dim/CD16pos phenotype (60, 72), they have been shown to share some phenotypic traits with CD56neg/CD16pos NK cells as well. These similar traits between “memory-like” and CD56neg/CD16pos NK cells are not supported by functional features, as the former are expected to display increased functional capacity while the latter are well known to be impaired in a number of effector functions. Further studies are needed to confirm if the KIRpos/NKG2Aneg/NKG2Cpos CD57pos NK cells represent the human memory NK cell counterpart and to test whether they share any of the CD56neg/CD16pos NK cell properties. Importantly, it would be interesting to determine whether continuous stimulation of NK cells by persistent, but undetectable viral replication, in infected individuals plays a role in maintaining these mature NK cell phenotypes.

Concluding Remarks

Viruses employ several strategies to escape from NK cell-mediated clearance of virally infected cells or secretion of anti-viral cytokines. In particular, it became clear that viruses are able to affect the functional status and the homeostasis of NK cells through the modulation/engagement of several surface receptors and through the expansion of unconventional NK cell subsets. Although many aspects of NK cell physiology have been disclosed by taking lessons from the physiopathology of viral infections, several fundamental questions still remain to be answered. First of all, the origin and the expansion of the CD56neg NK cells subset that represents the largest fraction of total NK cells in late stages of HIV-1 infection and that highly contributes to the lack of viral control and to disease progression. Disclosing the mechanisms underlying the high frequencies of this highly anergic NK cell population is key to better understand not only NK cell development but also to make it possible the manipulation of these cells in vitro in order to improve their anti-viral potential and provide a better control of viral replication and spreading.

Conflict of Interest Statement

The Review Editor Andrea De Maria declares that, despite being affiliated to the same institution as authors Emanuela Marcenaro and Domenico Mavilio, the review process was handled objectively and no conflict of interest exists. 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.

Acknowledgments

This research was supported by the Italian Ministry of Health (Bando Giovani Ricercatori GR-2008-1135082, and RF-ICH-2009-1299677 to Domenico Mavilio), by the Italian Association for Cancer Research (AIRC) (IG 14687 to Domenico Mavilio, MFAG 10607 to Enrico Lugli and Special Project 5 × 1000 9962 to Emanuela Marcenaro), by the European Union (Marie Curie Career Integration Grant 322093 to Enrico Lugli), by Fondazione Carige 2013 (to Emanuela Marcenaro), and by intramural program of Humanitas Research Hospital to Domenico Mavilio.

References

1. Biron CA, Byron KS, Sullivan JL. Severe herpesvirus infections in an adolescent without natural killer cells. N Engl J Med (1989) 320:1731–5. doi: 10.1056/NEJM198906293202605

CrossRef Full Text

2. Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, et al. Innate or adaptive immunity? The example of natural killer cells. Science (2011) 331:44–9. doi:10.1126/science.1198687

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

3. Moretta A, Bottino C, Vitale M, Pende D, Biassoni R, Mingari MC, et al. Receptors for HLA class-I molecules in human natural killer cells. Annu Rev Immunol (1996) 14:619–48. doi:10.1146/annurev.immunol.14.1.619

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

4. Moretta A, Bottino C, Vitale M, Pende D, Cantoni C, Mingari MC, et al. Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol (2001) 19:197–223. doi:10.1146/annurev.immunol.19.1.197

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

5. Long EO. Versatile signaling through NKG2D. Nat Immunol (2002) 3:1119–20. doi:10.1038/ni1202-1119

CrossRef Full Text

6. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol (2008) 9:503–10. doi:10.1038/ni1582

CrossRef Full Text

7. Smyth MJ, Godfrey DI, Trapani JA. A fresh look at tumor immunosurveillance and immunotherapy. Nat Immunol (2001) 2:293–9. doi:10.1038/86297

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

8. Lanier LL. NK cell recognition. Annu Rev Immunol (2005) 23:225–74. doi:10.1146/annurev.immunol.23.021704.115526

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

9. Michael T, Lotze AWT. Natural Killer Cells – Basic Science and Clinical Application. London: Elsevier (2010).

10. Fauci AS, Mavilio D, Kottilil S. NK cells in HIV infection: paradigm for protection or targets for ambush. Nat Rev Immunol (2005) 5:835–43. doi:10.1038/nri1760-c1

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

11. Gupta N, Arthos J, Khazanie P, Steenbeke TD, Censoplano NM, Chung EA, et al. Targeted lysis of HIV-infected cells by natural killer cells armed and triggered by a recombinant immunoglobulin fusion protein: implications for immunotherapy. Virology (2005) 332:491–7. doi:10.1016/j.virol.2004.12.018

CrossRef Full Text

12. Jost S, Altfeld M. Control of human viral infections by natural killer cells. Annu Rev Immunol (2013) 31:163–94. doi:10.1146/annurev-immunol-032712-100001

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

13. Marcenaro E, Carlomagno S, Pesce S, Della Chiesa M, Parolini S, Moretta A, et al. NK cells and their receptors during viral infections. Immunotherapy (2011) 3:1075–86. doi:10.2217/imt.11.99

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

14. Cerwenka A, Lanier LL. Natural killer cells, viruses and cancer. Nat Rev Immunol (2001) 1:41–9. doi:10.1038/35095564

CrossRef Full Text

15. Hudspeth K, Fogli M, Correia DV, Mikulak J, Roberto A, Della Bella S, et al. Engagement of NKp30 on Vdelta1 T cells induces the production of CCL3, CCL4, and CCL5 and suppresses HIV-1 replication. Blood (2012) 119:4013–6. doi:10.1182/blood-2011-11-390153

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

16. Brunetta E, Fogli M, Varchetta S, Bozzo L, Hudspeth KL, Marcenaro E, et al. Chronic HIV-1 viremia reverses NKG2A/NKG2C ratio on natural killer cells in patients with human cytomegalovirus co-infection. AIDS (2010) 24:27–34. doi:10.1097/QAD.0b013e3283328d1f

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

17. Brunetta E, Hudspeth KL, Mavilio D. Pathologic natural killer cell subset redistribution in HIV-1 infection: new insights in pathophysiology and clinical outcomes. J Leukoc Biol (2010) 88:1119–30. doi:10.1189/jlb.0410225

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

18. Degli-Esposti MA, Smyth MJ. Close encounters of different kinds: dendritic cells and NK cells take centre stage. Nat Rev Immunol (2005) 5:112–24. doi:10.1038/nri1549

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

19. Walzer T, Dalod M, Robbins SH, Zitvogel L, Vivier E. Natural killer cells and dendritic cells: “l’union fait la force”. Blood (2005) 106(7):2252–8. doi:10.1182/blood-2005-03-1154

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

20. Zitvogel L. Dendritic and natural killer cells cooperate in the control/switch of innate immunity. J Exp Med (2002) 195:F9–14. doi:10.1084/jem.20012040

CrossRef Full Text

21. Moretta A. Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol (2002) 2:957–64. doi:10.1038/nri956

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

22. Cooper MA, Fehniger TA, Fuchs A, Colonna M, Caligiuri MA. NK cell and DC interactions. Trends Immunol (2004) 25:47–52. doi:10.1016/j.it.2003.10.012

CrossRef Full Text

23. Mavilio D, Lombardo G, Kinter A, Fogli M, La Sala A, Ortolano S, et al. Characterization of the defective interaction between a subset of natural killer cells and dendritic cells in HIV-1 infection. J Exp Med (2006) 203:2339–50. doi:10.1084/jem.20060894

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

24. Vitale M, Della Chiesa M, Carlomagno S, Romagnani C, Thiel A, Moretta L, et al. The small subset of CD56brightCD16− natural killer cells is selectively responsible for both cell proliferation and interferon-gamma production upon interaction with dendritic cells. Eur J Immunol (2004) 34:1715–22. doi:10.1002/eji.200425100

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

25. Marcenaro E, Ferranti B, Moretta A. NK-DC interaction: on the usefulness of auto-aggression. Autoimmun Rev (2005) 4:520–5. doi:10.1016/j.autrev.2005.04.015

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

26. Bellora F, Castriconi R, Dondero A, Reggiardo G, Moretta L, Mantovani A, et al. The interaction of human natural killer cells with either unpolarized or polarized macrophages results in different functional outcomes. Proc Natl Acad Sci U S A (2010) 107:21659–64. doi:10.1073/pnas.1007654108

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

27. Nedvetzki S, Sowinski S, Eagle RA, Harris J, Vely F, Pende D, et al. Reciprocal regulation of human natural killer cells and macrophages associated with distinct immune synapses. Blood (2007) 109:3776–85. doi:10.1182/blood-2006-10-052977

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

28. Michel T, Hentges F, Zimmer J. Consequences of the crosstalk between monocytes/macrophages and natural killer cells. Front Immunol (2012) 3:403. doi:10.3389/fimmu.2012.00403

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

29. Thoren FB, Riise RE, Ousback J, Della Chiesa M, Alsterholm M, Marcenaro E, et al. Human NK cells induce neutrophil apoptosis via an NKp46- and Fas-dependent mechanism. J Immunol (2012) 188:1668–74. doi:10.4049/jimmunol.1102002

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

30. Costantini C, Calzetti F, Perbellini O, Micheletti A, Scarponi C, Lonardi S, et al. Human neutrophils interact with both 6-sulfo LacNAc+ DC and NK cells to amplify NK-derived IFN{gamma}: role of CD18, ICAM-1, and ICAM-3. Blood (2011) 117:1677–86. doi:10.1182/blood-2010-06-287243

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

31. Hudspeth K, Pontarini E, Tentorio P, Cimino M, Donadon M, Torzilli G, et al. The role of natural killer cells in autoimmune liver disease: a comprehensive review. J Autoimmun (2013) 46:55–65. doi:10.1016/j.jaut.2013.07.003

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

32. Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer- cell subsets. Trends Immunol (2001) 22:633–40. doi:10.1016/S1471-4906(01)02060-9

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

33. Brunetta E, Fogli M, Varchetta S, Bozzo L, Hudspeth KL, Marcenaro E, et al. The decreased expression of Siglec-7 represents an early marker of dysfunctional natural killer-cell subsets associated with high levels of HIV-1 viremia. Blood (2009) 114:3822–30. doi:10.1182/blood-2009-06-226332

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

34. Fauriat C, Ivarsson MA, Ljunggren HG, Malmberg KJ, Michaelsson J. Education of human natural killer cells by activating killer cell immunoglobulin-like receptors. Blood (2010) 115:1166–74. doi:10.1182/blood-2009-09-245746

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

35. De Maria A, Bozzano F, Cantoni C, Moretta L. Revisiting human natural killer cell subset function revealed cytolytic CD56(dim)CD16+ NK cells as rapid producers of abundant IFN-gamma on activation. Proc Natl Acad Sci U S A (2011) 108:728–32. doi:10.1073/pnas.1012356108

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

36. Varchetta S, Oliviero B, Mavilio D, Mondelli MU. Different combinations of cytokines and activating receptor stimuli are required for human natural killer cell functional diversity. Cytokine (2013) 62:58–63. doi:10.1016/j.cyto.2013.02.018

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

37. Robertson MJ. Role of chemokines in the biology of natural killer cells. J Leukoc Biol (2002) 71:173–83.

Pubmed Abstract | Pubmed Full Text

38. Carrega P, Ferlazzo G. Natural killer cell distribution and trafficking in human tissues. Front Immunol (2012) 3:347. doi:10.3389/fimmu.2012.00347

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

39. Parolini S, Santoro A, Marcenaro E, Luini W, Massardi L, Facchetti F, et al. The role of chemerin in the colocalization of NK and dendritic cell subsets into inflamed tissues. Blood (2007) 109:3625–32. doi:10.1182/blood-2006-08-038844

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

40. Mailliard RB, Alber SM, Shen H, Watkins SC, Kirkwood JM, Herberman RB, et al. IL-18-induced CD83+CCR7+ NK helper cells. J Exp Med (2005) 202:941–53. doi:10.1084/jem.20050128

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

41. Marcenaro E, Cantoni C, Pesce S, Prato C, Pende D, Agaugue S, et al. Uptake of CCR7 and acquisition of migratory properties by human KIR+ NK cells interacting with monocyte-derived DC or EBV cell lines: regulation by KIR/HLA-class I interaction. Blood (2009) 114:4108–16. doi:10.1182/blood-2009-05-222265

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

42. Marcenaro E, Pesce S, Sivori S, Carlomagno S, Moretta L, Moretta A. KIR2DS1-dependent acquisition of CCR7 and migratory properties by human NK cells interacting with allogeneic HLA-C2+ DCs or T-cell blasts. Blood (2013) 121:3396–401. doi:10.1182/blood-2012-09-458752

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

43. Bjorkstrom NK, Ljunggren HG, Sandberg JK. CD56 negative NK cells: origin, function, and role in chronic viral disease. Trends Immunol (2010) 31:401–6. doi:10.1016/j.it.2010.08.003

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

44. Hu PF, Hultin LE, Hultin P, Hausner MA, Hirji K, Jewett A, et al. Natural killer cell immunodeficiency in HIV disease is manifest by profoundly decreased numbers of CD16+CD56+ cells and expansion of a population of CD16dimCD56− cells with low lytic activity. J Acquir Immune Defic Syndr Hum Retrovirol (1995) 10:331–40. doi:10.1097/00042560-199511000-00005

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

45. Mavilio D, Benjamin J, Daucher M, Lombardo G, Kottilil S, Planta MA, et al. Natural killer cells in HIV-1 infection: dichotomous effects of viremia on inhibitory and activating receptors and their functional correlates. Proc Natl Acad Sci U S A (2003) 100:15011–6. doi:10.1073/pnas.2336091100

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

46. Mavilio D, Lombardo G, Benjamin J, Kim D, Follman D, Marcenaro E, et al. Characterization of CD56-/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals. Proc Natl Acad Sci U S A (2005) 102:2886–91. doi:10.1073/pnas.0409872102

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

47. Fogli M, Mavilio D, Brunetta E, Varchetta S, Ata K, Roby G, et al. Lysis of endogenously infected CD4+ T cell blasts by rIL-2 activated autologous natural killer cells from HIV-infected viremic individuals. PLoS Pathog (2008) 4:e1000101. doi:10.1371/journal.ppat.1000101

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

48. De Maria A, Fogli M, Costa P, Murdaca G, Puppo F, Mavilio D, et al. The impaired NK cell cytolytic function in viremic HIV-1 infection is associated with a reduced surface expression of natural cytotoxicity receptors (NKp46, NKp30 and NKp44). Eur J Immunol (2003) 33:2410–8. doi:10.1002/eji.200324141

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

49. Barker E, Martinson J, Brooks C, Landay A, Deeks S. Dysfunctional natural killer cells, in vivo, are governed by HIV viremia regardless of whether the infected individual is on antiretroviral therapy. AIDS (2007) 21:2363–5. doi:10.1097/QAD.0b013e3282f1d658

CrossRef Full Text

50. Tarazona R, Casado JG, Delarosa O, Torre-Cisneros J, Villanueva JL, Sanchez B, et al. Selective depletion of CD56(dim) NK cell subsets and maintenance of CD56(bright) NK cells in treatment-naive HIV-1-seropositive individuals. J Clin Immunol (2002) 22:176–83. doi:10.1023/A:1015476114409

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

51. Iannello A, Debbeche O, Samarani S, Ahmad A. Antiviral NK cell responses in HIV infection: II. Viral strategies for evasion and lessons for immunotherapy and vaccination. J Leukoc Biol (2008) 84:27–49. doi:10.1189/jlb.0907649

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

52. Marcenaro E, Carlomagno S, Pesce S, Moretta A, Sivori S. NK/DC crosstalk in anti-viral response. Adv Exp Med Biol (2012) 946:295–308. doi:10.1007/978-1-4614-0106-3_17

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

53. Alter G, Teigen N, Davis BT, Addo MM, Suscovich TJ, Waring MT, et al. Sequential deregulation of NK cell subset distribution and function starting in acute HIV-1 infection. Blood (2005) 106:3366–9. doi:10.1182/blood-2005-03-1100

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

54. Varchetta S, Lusso P, Hudspeth K, Mikulak J, Mele D, Paolucci S, et al. Sialic acid-binding Ig-like lectin-7 interacts with HIV-1 gp120 and facilitates infection of CD4pos T cells and macrophages. Retrovirology (2013) 10:154. doi:10.1186/1742-4690-10-154

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

55. Rempel H, Calosing C, Sun B, Pulliam L. Sialoadhesin expressed on IFN-induced monocytes binds HIV-1 and enhances infectivity. PLoS One (2008) 3:e1967. doi:10.1371/journal.pone.0001967

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

56. Zou Z, Chastain A, Moir S, Ford J, Trandem K, Martinelli E, et al. Siglecs facilitate HIV-1 infection of macrophages through adhesion with viral sialic acids. PLoS One (2011) 6:e24559. doi:10.1371/journal.pone.0024559

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

57. Izquierdo-Useros N, Lorizate M, Puertas MC, Rodriguez-Plata MT, Zangger N, Erikson E, et al. Siglec-1 is a novel dendritic cell receptor that mediates HIV-1 trans-infection through recognition of viral membrane gangliosides. PLoS Biol (2012) 10:e1001448. doi:10.1371/journal.pbio.1001448

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

58. Gonzalez VD, Falconer K, Michaelsson J, Moll M, Reichard O, Alaeus A, et al. Expansion of CD56− NK cells in chronic HCV/HIV-1 co-infection: reversion by antiviral treatment with pegylated IFNalpha and ribavirin. Clin Immunol (2008) 128:46–56. doi:10.1016/j.clim.2008.03.521

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

59. Gonzalez VD, Falconer K, Bjorkstrom NK, Blom KG, Weiland O, Ljunggren HG, et al. Expansion of functionally skewed CD56-negative NK cells in chronic hepatitis C virus infection: correlation with outcome of pegylated IFN-alpha and ribavirin treatment. J Immunol (2009) 183:6612–8. doi:10.4049/jimmunol.0901437

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

60. Della Chiesa M, Falco M, Podesta M, Locatelli F, Moretta L, Frassoni F, et al. Phenotypic and functional heterogeneity of human NK cells developing after umbilical cord blood transplantation: a role for human cytomegalovirus? Blood (2012) 119:399–410. doi:10.1182/blood-2011-08-372003

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

61. Bjorkstrom NK, Lindgren T, Stoltz M, Fauriat C, Braun M, Evander M, et al. Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus. J Exp Med (2011) 208:13–21. doi:10.1084/jem.20100762

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

62. Cruz AR, Ramirez LG, Zuluaga AV, Pillay A, Abreu C, Valencia CA, et al. Immune evasion and recognition of the syphilis spirochete in blood and skin of secondary syphilis patients: two immunologically distinct compartments. PLoS Negl Trop Dis (2012) 6:e1717. doi:10.1371/journal.pntd.0001717

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

63. Wiesmayr S, Webber SA, Macedo C, Popescu I, Smith L, Luce J, et al. Decreased NKp46 and NKG2D and elevated PD-1 are associated with altered NK-cell function in pediatric transplant patients with PTLD. Eur J Immunol (2012) 42:541–50. doi:10.1002/eji.201141832

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

64. Nguyen S, Morel V, Le Garff-Tavernier M, Bolgert F, Leblond V, Debre P, et al. Persistence of CD16+/CD56-/2B4+ natural killer cells: a highly dysfunctional NK subset expanded in ocular myasthenia gravis. J Neuroimmunol (2006) 179:117–25. doi:10.1016/j.jneuroim.2006.05.028

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

65. Antonioli CM, Airo P. Dermatomyositis associated with lymphoproliferative disorder of NK cells and occult small cell lung carcinoma. Clin Rheumatol (2004) 23:239–41. doi:10.1007/s10067-003-0814-2

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

66. Gaddy J, Risdon G, Broxmeyer HE. Cord blood natural killer cells are functionally and phenotypically immature but readily respond to interleukin-2 and interleukin-12. J Interferon Cytokine Res (1995) 15:527–36. doi:10.1089/jir.1995.15.527

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

67. Gaddy J, Broxmeyer HE. Cord blood CD16+56− cells with low lytic activity are possible precursors of mature natural killer cells. Cell Immunol (1997) 180:132–42. doi:10.1006/cimm.1997.1175

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

68. Bradstock KF, Luxford C, Grimsley PG. Functional and phenotypic assessment of neonatal human leucocytes expressing natural killer cell-associated antigens. Immunol Cell Biol (1993) 71(Pt 6):535–42. doi:10.1038/icb.1993.59

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

69. Jacobson A, Bell F, Lejarcegui N, Mitchell C, Frenkel L, Horton H. Healthy neonates possess a CD56-negative NK cell population with reduced anti-viral activity. PLoS One (2013) 8:e67700. doi:10.1371/journal.pone.0067700

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

70. Freud AG, Caligiuri MA. Human natural killer cell development. Immunol Rev (2006) 214:56–72. doi:10.1111/j.1600-065X.2006.00451.x

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

71. Milush JM, Lopez-Verges S, York VA, Deeks SG, Martin JN, Hecht FM, et al. CD56negCD16(+) NK cells are activated mature NK cells with impaired effector function during HIV-1 infection. Retrovirology (2013) 10:158. doi:10.1186/1742-4690-10-158

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

72. Lopez-Verges S, Milush JM, Schwartz BS, Pando MJ, Jarjoura J, York VA, et al. Expansion of a unique CD57(+)NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proc Natl Acad Sci U S A (2011) 108:14725–32. doi:10.1073/pnas.1110900108

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

73. Bhat R, Watzl C. Serial killing of tumor cells by human natural killer cells – enhancement by therapeutic antibodies. PLoS One (2007) 2:e326. doi:10.1371/journal.pone.0000326

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

74. Novershtern N, Subramanian A, Lawton LN, Mak RH, Haining WN, McConkey ME, et al. Densely interconnected transcriptional circuits control cell states in human hematopoiesis. Cell (2011) 144:296–309. doi:10.1016/j.cell.2011.01.004

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

75. Bukowski JF, Woda BA, Welsh RM. Pathogenesis of murine cytomegalovirus infection in natural killer cell-depleted mice. J Virol (1984) 52:119–28.

Pubmed Abstract | Pubmed Full Text

76. Noriega V, Redmann V, Gardner T, Tortorella D. Diverse immune evasion strategies by human cytomegalovirus. Immunol Res (2012) 54:140–51. doi:10.1007/s12026-012-8304-8

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

77. Groh V, Bahram S, Bauer S, Herman A, Beauchamp M, Spies T. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc Natl Acad Sci U S A (1996) 93:12445–50. doi:10.1073/pnas.93.22.12445

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

78. Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddell SR, Spies T. Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat Immunol (2001) 2:255–60. doi:10.1038/85321

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

79. Cosman D, Mullberg J, Sutherland CL, Chin W, Armitage R, Fanslow W, et al. ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity (2001) 14:123–33. doi:10.1016/S1074-7613(01)00095-4

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

80. Ariza-Heredia EJ, Nesher L, Chemaly RF. Cytomegalovirus diseases after hematopoietic stem cell transplantation: a mini-review. Cancer Lett (2014) 342:1–8. doi:10.1016/j.canlet.2013.09.004

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

81. Bosch M, Khan FM, Storek J. Immune reconstitution after hematopoietic cell transplantation. Curr Opin Hematol (2012) 19:324–35. doi:10.1097/MOH.0b013e328353bc7d

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

82. Foley B, Cooley S, Verneris MR, Curtsinger J, Luo X, Waller EK, et al. Human cytomegalovirus (CMV)-induced memory-like NKG2C(+) NK cells are transplantable and expand in vivo in response to recipient CMV antigen. J Immunol (2012) 189:5082–8. doi:10.4049/jimmunol.1201964

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

83. Della Chiesa M, Muccio L, Moretta A. CMV induces rapid NK cell maturation in HSCT recipients. Immunol Lett (2013) 155:11–3. doi:10.1016/j.imlet.2013.09.020

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

84. Della Chiesa M, Falco M, Bertaina A, Muccio L, Alicata C, Frassoni F, et al. Human cytomegalovirus infection promotes rapid maturation of NK cells expressing activating killer Ig-like receptor in patients transplanted with NKG2C−/− umbilical cord blood. J Immunol (2014) 192:1471–9. doi:10.4049/jimmunol.1302053

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

85. Solana R, Tarazona R, Aiello AE, Akbar AN, Appay V, Beswick M, et al. CMV and Immunosenescence: from basics to clinics. Immun Ageing (2012) 9:23. doi:10.1186/1742-4933-9-23

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

86. Della Chiesa M, Falco M, Muccio L, Bertaina A, Locatelli F, Moretta A. Impact of HCMV infection on NK cell development and function after HSCT. Front Immunol (2013) 4:458. doi:10.3389/fimmu.2013.00458

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

87. Hazenberg MD, Hamann D, Schuitemaker H, Miedema F. T cell depletion in HIV-1 infection: how CD4+ T cells go out of stock. Nat Immunol (2000) 1:285–9. doi:10.1038/79724

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

88. Sun JC, Beilke JN, Lanier LL. Adaptive immune features of natural killer cells. Nature (2009) 457:557–61. doi:10.1038/nature07665

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

89. Guma M, Cabrera C, Erkizia I, Bofill M, Clotet B, Ruiz L, et al. Human cytomegalovirus infection is associated with increased proportions of NK cells that express the CD94/NKG2C receptor in aviremic HIV-1-positive patients. J Infect Dis (2006) 194:38–41. doi:10.1086/504719

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

90. Kuijpers TW, Baars PA, Dantin C, van den Burg M, van Lier RA, Roosnek E. Human NK cells can control CMV infection in the absence of T cells. Blood (2008) 112:914–5. doi:10.1182/blood-2008-05-157354

CrossRef Full Text

91. Foley B, Cooley S, Verneris MR, Pitt M, Curtsinger J, Luo X, et al. Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function. Blood (2012) 119:2665–74. doi:10.1182/blood-2011-10-386995

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

92. Della Chiesa M, Marcenaro E, Sivori S, Carlomagno S, Pesce S, Moretta A. Human NK cell response to pathogens. Semin Immunol (2014) 26:152–60. doi:10.1016/j.smim.2014.02.001

CrossRef Full Text

93. Cook M, Briggs D, Craddock C, Mahendra P, Milligan D, Fegan C, et al. Donor KIR genotype has a major influence on the rate of cytomegalovirus reactivation following T-cell replete stem cell transplantation. Blood (2006) 107:1230–2. doi:10.1182/blood-2005-03-1039

Pubmed Abstract | Pubmed Full Text | CrossRef Full Text

Keywords: viral infection, immune escape, immune activation, innate immune response, physiophysiological interaction

Citation: Lugli E, Marcenaro E and Mavilio D (2014) NK cell subset redistribution during the course of viral infections. Front. Immunol. 5:390. doi: 10.3389/fimmu.2014.00390

Received: 27 February 2014; Accepted: 01 August 2014;
Published online: 14 August 2014.

Edited by:

Daniel Olive, INSERM UMR 891 Institut Paoli Calmettes, France

Reviewed by:

Cristina Cerboni, Sapienza University of Rome, Italy
Andrea De Maria, Università degli Studi di Genova, Italy

Copyright: © 2014 Lugli, Marcenaro and Mavilio. 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: Domenico Mavilio, Unit of Clinical and Experimental Immunology, Department of Medical Biotechnologies and Translational Medicine, Humanitas Clinical and Research Center, University of Milan School of Medicine, Via Alessandro Manzoni 113, 20089 Rozzano, Milan, Italy e-mail: domenico.mavilio@humanitas.it

Enrico Lugli, Emanuela Marcenaro and Domenico Mavilio have contributed equally to this work.