Abstract
Necrotizing enterocolitis (NEC) is a destructive gastrointestinal disease primarily affecting preterm babies. Despite advancements in neonatal care, NEC remains a significant cause of morbidity and mortality in neonatal intensive care units worldwide and the etiology of NEC is still unclear. Risk factors for NEC include prematurity, very low birth weight, feeding with formula, intestinal dysbiosis and bacterial infection. A review of the literature would suggest that supplementation of prebiotics and probiotics prevents NEC by altering the immune responses. Innate T cells, a highly conserved subpopulation of T cells that responds quickly to stimulation, develops differently from conventional T cells in neonates. This review aims to provide a succinct overview of innate T cells in neonates, encompassing their phenotypic characteristics, functional roles, likely involvement in the pathogenesis of NEC, and potential therapeutic implications.
Introduction
Necrotizing enterocolitis (NEC) is a devastating disease that affects neonates born prematurely. Approximately 10% of infants are born pre-term, and about 7% of them develop NEC (1). While etiology of NEC is unknown, several risk factors have been previously reported: prematurity, very low birth weight, formula feeding, microbial dysbiosis and bacterial infection (2–7). The current treatment of NEC includes cessation of enteral feeding, use of broad-spectrum antibiotics, and parenteral administration of nutrition. About 50% of infants with NEC progress to requiring surgical intervention due to intestinal ischemia and necrosis, which is often associated with high mortality and long-term complications including intestinal stricture, short-gut syndrome, and neurodevelopmental delays (1, 8). Discovering new approaches to treat NEC medically is imperative to avoid disease progression and surgical interventions.
The diagnosis, classification, management, outcome, and complications of NEC have been summarized in many great review articles (2–6). This review focuses on exploring the possibility therapeutic role of innate T cells for NEC.
Unique characteristics of neonatal immune response
Tolerogenic nature
The neonatal immune system can be characterized as tolerogenic, immature, and naïve. During pregnancy, microchimerism occurs, leading to the presence of maternal cells in the fetuses and vice versa. As a result, fetal immune cells are tolerant towards maternal antigens, while maternal immune cells and antibodies are vertically transferred to offspring (9, 10). Due to this tolerogenic nature and inherent bias toward Th2-cell polarization, the developing immune system in neonates can be more susceptible to infections (11, 12).
Immaturity and naivety
Neonatal immune cells are quantitatively fewer and qualitatively different from their adult immune cells (12, 13). As a result, maternal immune cells and antibodies circulate in offspring long after birth and impact neonatal immune responses (13–15). While maternal IgG is critical in preventing bacterial infection in neonates (16), the presence of maternal antibodies worsen the intrinsic defect of the infant’s primary antibody response but does not appear to affect their T cell response (13). Though neonatal T cells are mostly recent thymic emigrants, less antigen-experienced, and produce less IL-2 and IFN-γ (17), these cells may be more sensitive to cytokines than to antigen stimulations due to higher expression of cytokine receptors on their cell surface (18).
Impact of microchimerism
The adaptive immune system in neonates is naïve and defective due to limited exposure to antigens and the tolerogenic environment in utero (19), therefore innate immunity is important in providing protection from infections (12, 20) despite its immaturity and hyporesponsiveness to stimulations (11, 21). A recent study showed that maternal microchimeric cells are enriched in fetal bone marrow and favor fetal monocyte differentiation (22), suggesting maternal/offspring microchimerism also affects neonatal innate immunity.
Neonatal T cells have full potential
Many investigations suggest that fetuses and neonates are capable of mounting robust T cell responses (13, 19). Early in life, neonates experience rapid growth and may allocate energy towards growth rather than mounting an immune response, leading to environmental enteric dysfunction (EED). Neonates need to maintain a balance between host defense against pathogens and other essential physiological processes (17).
While significant knowledge in neonatal immunity has been acquired, little is known about neonatal innate T cells and their role in the immune responses in neonatal diseases.
Innate T cells in neonates
Characteristics of innate T cells
Conventional T cells express highly diverse T-cell receptors (TCRs) and respond to peptide antigens presented by polymorphic MHC class I or II molecules. In contrast, innate T cells often have limited TCR diversity and predominantly recognize non-peptide antigens presented by monomorphic non-MHC molecules (23). Many of the non-peptide antigens that activate innate T cells are microbially derived (24–31). Therefore, their development and function are changed by the microbiome (32–34).
There are three subsets of innate T cells: Natural Killer T (NKT) cells, Mucosal-Associated Invariant T (MAIT) cells and Gamma Delta (γδ) T cells. NKT and MAIT cells are mostly semi-invariant αβ T cells. All three types of innate T cells develop in the thymus and localize in non-lymphoid tissues such as the liver, lung, and intestine (24, 35).
As shown in Table 1, innate T cells share some common characteristics, such as their ability to bridge the innate and adaptive immune systems by quickly responding to antigens and producing large amounts of pro- and anti-inflammatory cytokines (23). The development of all three types of innate T cells is regulated by the same transcription factor, PLZF (promyelocytic leukemia zinc finger; ZBTB16) (35, 53–55). Transcriptomic analyses have demonstrated that both NKT and MAIT cells are more similar with one another compared to conventional T cells (56, 57). While all innate T cells express IL-12 receptor (IL-12R), IL-18R and other surface markers (24, 51), both NKT and MAIT cells also express NK and T cell markers (51). The similar transcriptomic profiles of NKT and MAIT cells are likely acquired by their residence in the thymus (56).
Table 1
| NKT cells | MAIT cells | γδ T cells | References | |
|---|---|---|---|---|
| Maturation marker | CD45RO+ CD161+CD25+CD122+ CD127+ | CD45RO+CD161+CD25+ | CD27+CD28+ | (36, 37) |
| Frequency in infants | <0.1% of CD3 T cells in cord blood | ~0.1% of CD3 T cells in cord blood | ~2% of CD3 T cells in cord blood | (36, 37) |
| Frequency in neonatal mice | Little is known | undetectable | 3-4 times of αβ T cells in small intestine | (38, 39) |
| Microbial antigens/ligand | Microbial lipids such as α-glucuronosylceramide (GSL-1) | Microbial vitamin B metabolites | Phosphoantigens, Butyrophilins | (24, 40, 41) |
| Cytokine secretion | IFN-γ, IL-4 | IFN-γ, IL-22 | IFN-γ, TNF-α, IL-10 | (42–47) |
| NEC impact | unknown | More MAIT cells accumulated in NEC intestines | Reduced in NEC | (48–50) |
| Common Characteristics | a) Limited TCR diversity; b) non-peptide antigens; c) enriched in non-lymphoid organs; d) developed in thymus; e) expressing IL-12 receptor and IL-18 receptor; f) PLZF as transcription factor; g) more cytokine production upon stimulation comparing to conventional T cells; h) proportion in T cells negatively correlates with gestational age; i) hyperproliferative potential | (23, 24, 35, 3642–45, 51, 52) | ||
Comparison of fetal/neonatal innate T cells.
Early in life, all three types of innate T cells seem to be more responsive and mature than conventional T cells in responding to stimulation (24, 42–44). These innate T cells are speculated to play important roles in tissue homeostasis and fighting against infection during early life when conventional T cells are still naïve and immature (58).
Neonatal NKT cells
NKT cells are innate T cells that can be activated by lipid antigens, with CD1d, an MHC class I-like molecule, acting as the antigen presenting molecule (59–62). The most potent lipid antigen for NKT cells is alpha-Galactosylceramide (a-GalCer, KRN7000), which is a synthetic glycolipid derived from the marine sponge Agelas mauritianus (63, 64). NKT cells can also be activated by various endogenous and microbial lipid antigens such as iGb3, sulfatide, and α-glucuronosylceramide (GSL-1) (28, 40, 65, 66). Activated NKT cells may be utilized in vaccine development and the treatment of conditions like autoimmune diseases, graft-versus-host disease, infections, neurological diseases, and cancer (67–77).
NKT cells are either CD4+ or CD4-CD8- T cells. Based on TCR usage, NKT cells can be further categorized as Type I (invariant TCR) and the much less studied Type II (variable CD1d-restricted TCR) NKT cells. In this review only type I NKT cells related work is discussed.
Studies have shown that a low number of neonatal NKT cells are present in cord blood (45, 78) and they are less responsive to stimulation compared to adult NKT cells (45). However, neonatal NKT cells were more responsive to stimulation compared to neonatal conventional T cells (45). The population of neonatal NKT cells was higher in the blood of day 14 preterm infants compared to those from age-matched full-term infants. In the subsequent 2-3 weeks, however, that higher proportion of NKT cells decreases to a level similar to that of full-term infants. This is likely due to gestational development because the proportion of CD3+ T cells expands and positively correlates with gestational age (52). The proportion of NKT cells in the blood should expand as infants grow older since the proportion of NKT cells in adult blood is much higher than that in cord blood (45).
Neonates have a Th-2 biased immunity with neonatal NKT cells producing more IL-4 than IFN-γ (46, 47). Interestingly, NKT cells are enriched in the fetal small intestine. These small intestinal NKT cells, different from NKT cells from other fetal organs, express mature markers and IFN-γ upon stimulation, resembling adult NKT cells (44).
As shown in Table 1, not much is known about the frequency of neonatal NKT cells in mice.
Neonatal MAIT cells
MAIT cells predominantly recognize non-peptide microbial antigens presented by monomorphic MHC class I-like molecule (MR1) (23, 30, 79). MAIT cells express limited TCR diversity (Vα19 in mice, Vα7.2 in humans with limited variation of TCR-β chains). The research of MAIT cell antigens experienced a breakthrough when 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) was identified and remains the most potent MAIT cell agonist to date (31, 41, 80). MAIT cells are mostly CD8+ or CD4-CD8- T cells. Emerging research demonstrates that MAIT cells are involved in many conditions, such as infection, cancer, tissue repair, autoimmunity, inflammation, and metabolic diseases (81–89).
Data on how gestational age impacts MAIT cell levels is conflicting. One study suggests that the proportion of neonatal MAIT cells is low and does not seem to be affected by gestational age ranged 23 to 28 weeks (52). However, another study using cord blood from broader range of gestational ages (24 weeks to full term) showed that the proportion of MAIT cells in CD3+ T cells negatively correlated with gestational age (36). Currently, there are two ways to identify human MAIT cells: CD3+Vα7.2+ CD161high T and CD3+MR1:5-OP-RU tetramer+ cells. In adult blood, these two populations almost fully overlap. However, in cord blood, only a small portion of CD3+Vα7.2+ CD161high T cells are also MR1:5-OP-RU tetramer+ (36, 53). This is likely due to specific expansion after encountering microbial antigens. Cord blood-derived MAIT cells consistently are more capable to proliferate upon stimulation compared to adult MAIT cells (36). Allogeneic hematopoietic cell transplantation study showed expansion of MAIT cells in recipients after cord blood transplantation but not in adult bone-marrow or peripheral blood stem cell transplantations, supporting the high proliferative capacity of neonatal MAIT cells (90).
Mouse MAIT cell studies have been lagging due to the scarcity of mouse MAIT cells. To solve this problem, a wild-derived inbred CAST/EiJ mouse model was discovered with frequencies of MAIT cells 20 times more than those in C57BL/6J mice (38). MAIT cells also increase significantly in the transgenic mice expressing the TCR Vα19, but its application is limited due to high non-specific binding of MR1:5-OP-RU tetramer in other T cells (91–93). Like human MAIT cells, mouse MAIT cells are almost undetectable at birth but expand significantly after encountering the developing microbiome (38).
Neonatal γδ T cells
Most mammalian T cells express αβ TCR. A small population of T cells express gamma and delta (γδ) TCR and these cells are called γδ T cells. The antigen presenting molecule for γδ T cells is not known. γδ TCR may interact with antigens in an antibody/antigen binding fashion (24, 94, 95). The functions of γδ T cells include immune surveillance, thermogenesis, and tissue homeostasis (96). γδ T cells are known to be important for maintaining mucosal tolerance (97, 98). Although similar numbers of γδ T cells can be found in the intestine of germ-free and specific pathogen-free mice (99), the crosstalk between microbiome and γδ T cells is important for the effector function of γδ T cells (32). Removal of gut microbiome by antibiotic treatment in drinking water impairs oral tolerance and also transiently removes intestinal γδ T cells.
Neonatal γδ T cells are Th2-prone and more naïve than adult γδ T cells, but more Th1-prone compared to neonatal αβ T cells. Thus, it seems reasonable to hypothesize that neonatal γδ T cells may be key providers of immunoprotection and immunomodulation in the perinatal period (42). γδ intraepithelial lymphocytes (IEL) are the first T-cell subset present in the intestine during embryogenesis (39, 100). Neonatal mouse γδ IELs were found to produce higher levels of cytokines, such as IFN-γ and IL-10, as compared to neonatal αβ IELs and adult γδ IELs, indicating enhanced activity of γδ IELs during early life (39).
Neonatal γδ T cells are more diverse compared to adult γδ T cells. The dominant Vγ9Vδ2 subset in human adult blood is due to the post-natal expansion of cells expressing unique CDR3 formed in response to encountering phosphor-antigens derived from the microbe-specific isoprenoid synthesis pathway. During mouse embryonic development, there are waves of γδ T cell development that start as early as day 15 of gestation so most peripheral tissues are colonized by long-lived γδ T cells early in life (96). The first wave of mouse γδ T cells are dendritic epidermal T cells (DETCs). These DETCs migrate to mouse skin and proliferate there during fetal development (24, 96). While some γδ T cells can be restored in 2 weeks in adult mice, fetal γδ T cells cannot be regenerated in the adult thymus (24).
Similar to neonatal NKT cells, the proportion of neonatal γδ T cells are larger in the blood from preterm infants than that from full-term infants, and the proportion of γδ T cells decreases to a similar level as that from full-term infants in the next 2-4 weeks (52). This is likely due to the expansion of CD3+ T cells in late gestational stages.
The role of innate T cells in NEC
Gut microbial community perturbations are the most consequential risk factor for NEC (101). The intestinal microbiome of preterm infants is distinct and less diverse than that of term-born infants. Interestingly, the gut microbiome in preterm infants seems to have an orderly progression where the bacterial classes switch from Bacilli to Gammaproteobacteria to Clostridia, and is minimally influenced by mode of delivery, antibiotics, or feeds (101, 102).
It is not clear how the bacterial class switch in preterm infants increases their risk of developing NEC but analysis of gene expression analysis in NEC tissues does reveal an altered immune response (48, 103–106). The microbial dysbiosis in NEC likely alters the development of innate T cells given the microbiome’s known influence on innate T cell maturation, activation, and expansion via changes in microbial antigens and modulation of the mucosal microenvironment (32, 81, 107, 108). Immune cell development needs microbial exposure, but there seems to be a “window of opportunity” (17, 58, 109). Using mouse models, several groups have demonstrated that exposure to certain microbiome early in life defines hosts’ T cell functions in adulthood (17, 58, 109). It is reasonable to speculate that the microbial dysbiosis in NEC impacts not only neonatal immunity but also long-term immunity beyond when the disease is resolved.
Studies about the relationship between innate T cells and NEC are sparse. A recent report has shown that more MAIT cells accumulate in the intestine of NEC patients compared to control infants. However, these MAIT cells within NEC intestine are mostly CD4-CD8-, while MAIT cells from healthy intestine are mainly CD8αα+ MAIT cells (49). CD8αα+ MAIT cells are known to be more mature than CD4-CD8- or CD8αβ+ MAIT cells (43, 110). These results suggest that there are more immature MAIT cells residing in NEC intestines. Weitkamp et al. discovered significantly lower CD8 + γδ IEL in preterm infants with NEC compared to control infants, suggesting that γδ IELs depletion occurs during the development of NEC (39).
It is worth noting that a unique population of IELs, called innate CD8alpha (iCD8α) cells, that expresses the CD8αα homodimer and may be involved with NEC pathogenesis. Though neither T cells nor dendritic cells, they are IL-12R positive and responsive to stimulation by IL-12 and PMA/Ionomycin. iCD8α cells show capacity in antigen processing/presentation and protection from bacterial infection (111). iCD8α cells are also reduced in NEC patients compared to control infants, consistent with reduced CD8αα+ MAIT and CD8+ γδ T cells in NEC (39, 49, 111). These observations indicate mucosal CD8+ lymphocytes, either TCR+ (MAIT and γδ T cells) or TCR- (innate lymphoid cells) may be important in preventing NEC.
Deficiency of MR1 in neonatal mice renders protection from NEC pathogenesis (112) while TCRδ-deficient neonatal mice develop worse NEC disease compared to WT controls (39). These data suggest that innate T cells, probably altered by microbial dysbiosis, play a role in NEC pathogenesis (Figure 1A). Little is known how innate T cells may contribute to the pathogenesis of NEC. Innate T cells are known to bridge the innate and adaptive immune system and can mediate immune tolerance (113–116). It is speculated that the function of innate T cells may be altered with reduced immune tolerance due to microbial dysbiosis and immaturity in preterm infants. Another possible factor is IL-17 production that plays a critical role in pathogenesis of NEC (117). Innate T cells are known to produce IL-17 (118–120). Innate T cells from preterm infants may produce more IL-17 due to immaturity and microbial dysbiosis, contributing to NEC pathogenesis.
Figure 1
Conclusions and future direction
The current standard treatment regimen of NEC includes cessation of enteral feeding, institution of parenteral nutrition, initiating broad-spectrum antibiotics, respiratory support, and surgical intervention as needed (1). Human breastmilk has long been utilized as a way to reduce NEC (1). The expansion of Bifidobacteriaceae in gut microbiome after birth also decreases the risk of NEC (3, 100, 121). Human milk oligosaccharide (HMO) is important to bifidobacterial colonization, consistent with the observation that breast-feeding lowers the incidence of NEC (100). Prebiotics (e.g. human milk oligosaccharide) and probiotics (e.g. Bifidobacteria) are being investigated as potential preventative and therapeutics approaches for NEC (3, 7, 121, 122). A few acting mechanisms of probiotics in preventing NEC have been proposed (123), but little is known about how prebiotics and probiotics therapies may change innate T cells in NEC.
Because of their limited TCR diversity and monomorphism, innate T cells would be an off-the-shelf cell-based therapy with minimal graft-versus-host disease (124). Innate T cells can quickly respond to antigens and produce large amounts of pro- and anti-inflammatory cytokines to bridge the innate and adaptive immune systems (23, 51, 125–127). Innate T cells can also acquire effector T cell characteristics and accumulate in mucosal tissues early in life (42–44). IL-22 has been shown to alleviate NEC (128) and innate T cells are capable of producing IL-22 (43, 118). Genetic engineering technologies, such as CRISPR/Cre and CAR-T cells (76, 129–131), may facilitate the production of IL-22-producing γδ T and/or MAIT cells, even iCD8α IELs, for cell-based immunotherapy for NEC.
Contrarily, the accumulation of immature innate T cells in preterm infants may lead to the development of NEC. Blocking the activation of immature innate T cells may reduce the incidence of NEC. Antibodies for CD1d and MR1, the antigen presenting molecules for NKT and MAIT cells respectively, are effective in suppressing NKT and MAIT cell activation (132–134). These MR1 and CD1d specific antibodies may also be a potential avenue for further investigations in NEC immunotherapy.
Preterm infants are not developmentally primed to be colonized by microorganisms and the normal neonatal microbial adaptation may be hazardous in preterm infants (135). It is well-established that the development and maturation of innate T cells are influenced by the microbiome. The levels of innate T cells in preterm infants negatively correlates with gestational age (Figure 1B, Table 1) but the mechanism is unknown. Because the mother and offspring form a microchimer, innate T cells in fetus and preterm infants can be from fetal or maternal origin. The gut microbiome in preterm infants is transitional and different from term infants, but it is unclear exactly how the innate T cells in preterm infants are influenced by the altered gut microbiome. Future work should focus on identifying the origin of fetal and neonatal innate T cells and how their development and function are impacted by beneficial or pathogenic microbiome. The knowledge gained from this work will help facilitate the development of a novel innate T cell-based therapy for NEC.
Statements
Author contributions
JL: Writing – original draft, Writing – review & editing. KM: Writing – review & editing. SJ: Writing – review & editing. JL: Writing – review & editing. JB: Writing – review & editing. CS: Writing – review & editing. TM: Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
Conflict of interest
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.
Publisher’s note
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.
References
1
RichBSDolginSE. Necrotizing enterocolitis. Pediatr Rev (2017) 38(12):552–9. doi: 10.1542/pir.2017-0002
2
MarkelTAEngelstadHPoindexterBB. Predicting disease severity of necrotizing enterocolitis: how to identify infants for future novel therapies. J Clin Neonatol. (2014) 3(1):1–9. doi: 10.4103/2249-4847.128717
3
KimCSClaudEC. Necrotizing enterocolitis pathophysiology: how microbiome data alter our understanding. Clin Perinatol. (2019) 46(1):29–38. doi: 10.1016/j.clp.2018.10.003
4
FundoraJBGuhaPShoresDRPammiMMaheshwariA. Intestinal dysbiosis and necrotizing enterocolitis: assessment for causality using Bradford Hill criteria. Pediatr Res (2020) 87(2):235–48. doi: 10.1038/s41390-019-0482-9
5
NeuJWalkerWA. Necrotizing enterocolitis. N Engl J Med (2011) 364(3):255–64. doi: 10.1056/NEJMra1005408
6
AlganabiMLeeCBindiELiBPierroA. Recent advances in understanding necrotizing enterocolitis. F1000Res. (2019) 8:107. doi: 10.12688/f1000research.17228.1
7
Campos-MartinezAMExposito-HerreraJGonzalez-BolivarMFernandez-MarinEUberosJ. Evaluation of risk and preventive factors for necrotizing enterocolitis in premature newborns. A Systematic Rev Literature. Front Pediatr (2022) 10:874976. doi: 10.3389/fped.2022.874976
8
DruckerNAMcCullohCJLiBPierroABesnerGEMarkelTA. Stem cell therapy in necrotizing enterocolitis: Current state and future directions. Semin Pediatr Surg (2018) 27(1):57–64. doi: 10.1053/j.sempedsurg.2017.11.011
9
KinderJMStelzerIAArckPCWaySS. Immunological implications of pregnancy-induced microchimerism. Nat Rev Immunol (2017) 17(8):483–94. doi: 10.1038/nri.2017.38
10
AdamsKMNelsonJL. Microchimerism: an investigative frontier in autoimmunity and transplantation. Jama. (2004) 291(9):1127–31. doi: 10.1001/jama.291.9.1127
11
LevyO. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol (2007) 7(5):379–90. doi: 10.1038/nri2075
12
BashaSSurendranNPichicheroM. Immune responses in neonates. Expert Rev Clin Immunol (2014) 10(9):1171–84. doi: 10.1586/1744666X.2014.942288
13
AdkinsBLeclercCMarshall-ClarkeS. Neonatal adaptive immunity comes of age. Nat Rev Immunol (2004) 4(7):553–64. doi: 10.1038/nri1394
14
TouzotFDal-CortivoLVerkarreVLimACrucis-ArmengaudAMoshousDet al. Massive expansion of maternal T cells in response to EBV infection in a patient with SCID-Xl. Blood. (2012) 120(9):1957–9. doi: 10.1182/blood-2012-04-426833
15
MaloneySSmithAFurstDEMyersonDRupertKEvansPCet al. Microchimerism of maternal origin persists into adult life. J Clin Invest. (1999) 104(1):41–7. doi: 10.1172/JCI6611
16
SanidadKZAmirMAnanthanarayananASingarajuAShilandNBHongHSet al. Maternal gut microbiome-induced IgG regulates neonatal gut microbiome and immunity. Sci Immunol (2022) 7(72):eabh3816. doi: 10.1126/sciimmunol.abh3816
17
TorowNHandTWHornefMW. Programmed and environmental determinants driving neonatal mucosal immune development. Immunity. (2023) 56(3):485–99. doi: 10.1016/j.immuni.2023.02.013
18
RuddBD. Neonatal T cells: A reinterpretation. Annu Rev Immunol (2020) 38:229–47. doi: 10.1146/annurev-immunol-091319-083608
19
RackaityteEHalkiasJ. Mechanisms of fetal T cell tolerance and immune regulation. Front Immunol (2020) 11:588. doi: 10.3389/fimmu.2020.00588
20
KumarSKBhatBV. Distinct mechanisms of the newborn innate immunity. Immunol Lett (2016) 173:42–54. doi: 10.1016/j.imlet.2016.03.009
21
YuJCKhodadadiHMalikADavidsonBSalles ÉDSLBhatiaJet al. Innate immunity of neonates and infants. Front Immunol (2018) 9:1759. doi: 10.3389/fimmu.2018.01759
22
StelzerIAUrbschatCSchepanskiSThieleKTriviaiIWieczorekAet al. Vertically transferred maternal immune cells promote neonatal immunity against early life infections. Nat Commun (2021) 12(1):4706. doi: 10.1038/s41467-021-24719-z
23
GodfreyDIUldrichAPMcCluskeyJRossjohnJMoodyDB. The burgeoning family of unconventional T cells. Nat Immunol (2015) 16(11):1114–23. doi: 10.1038/ni.3298
24
VermijlenDPrinzI. Ontogeny of innate T lymphocytes - some innate lymphocytes are more innate than others. Front Immunol (2014) 5:486. doi: 10.3389/fimmu.2014.00486
25
WuDXingGWPolesMAHorowitzAKinjoYSullivanBet al. Bacterial glycolipids and analogs as antigens for CD1d-restricted NKT cells. Proc Natl Acad Sci U S A. (2005) 102(5):1351–6. doi: 10.1073/pnas.0408696102
26
KinjoYWuDKimGXingGWPolesMAHoDDet al. Recognition of bacterial glycosphingolipids by natural killer T cells. Nature. (2005) 434(7032):520–5. doi: 10.1038/nature03407
27
MattnerJDebordKLIsmailNGoffRDCantuC3rdZhouDet al. Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature. (2005) 434(7032):525–9. doi: 10.1038/nature03408
28
SriramVDuWGervay-HagueJBrutkiewiczRR. Cell wall glycosphingolipids of Sphingomonas paucimobilis are CD1d-specific ligands for NKT cells. Eur J Immunol (2005) 35(6):1692–701. doi: 10.1002/eji.200526157
29
AltincicekBMollJCamposNFoersterGBeckEHoefflerJFet al. Cutting edge: human gamma delta T cells are activated by intermediates of the 2-C-methyl-D-erythritol 4-phosphate pathway of isoprenoid biosynthesis. J Immunol (2001) 166(6):3655–8. doi: 10.4049/jimmunol.166.6.3655
30
Le BourhisLMartinEPeguilletIGuihotAFrouxNCoreMet al. Antimicrobial activity of mucosal-associated invariant T cells. Nat Immunol (2010) 11(8):701–8. doi: 10.1038/ni.1890
31
Kjer-NielsenLPatelOCorbettAJLe NoursJMeehanBLiuLet al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature. (2012) 491(7426):717–23. doi: 10.1038/nature11605
32
PapottoPHYilmazBSilva-SantosB. Crosstalk between gammadelta T cells and the microbiota. Nat Microbiol (2021) 6(9):1110–7. doi: 10.1038/s41564-021-00948-2
33
SuXGaoYYangR. Gut microbiota derived bile acid metabolites maintain the homeostasis of gut and systemic immunity. Front Immunol (2023) 14:1127743. doi: 10.3389/fimmu.2023.1127743
34
JabeenMFHinksTSC. MAIT cells and the microbiome. Front Immunol (2023) 14:1127588. doi: 10.3389/fimmu.2023.1127588
35
PellicciDGKoayHFBerzinsSP. Thymic development of unconventional T cells: how NKT cells, MAIT cells and gammadelta T cells emerge. Nat Rev Immunol (2020) 20(12):756–70. doi: 10.1038/s41577-020-0345-y
36
Ben YoussefGTourretMSalouMGhazarianLHoudouinVMondotSet al. Ontogeny of human mucosal-associated invariant T cells and related T cell subsets. J Exp Med (2018) 215(2):459–79. doi: 10.1084/jem.20171739
37
van der HeidenMBjorkanderSRahman QaziKBittmannJHellLJenmalmMCet al. Characterization of the gammadelta T-cell compartment during infancy reveals clear differences between the early neonatal period and 2 years of age. Immunol Cell Biol (2020) 98(1):79–87. doi: 10.1111/imcb.12303
38
CuiYFranciszkiewiczKMburuYKMondotSLe BourhisLPremelVet al. Mucosal-associated invariant T cell-rich congenic mouse strain allows functional evaluation. J Clin Invest. (2015) 125(11):4171–85. doi: 10.1172/JCI82424
39
WeitkampJHRosenMJZhaoZKoyamaTGeemDDenningTLet al. Small intestinal intraepithelial TCRgammadelta+ T lymphocytes are present in the premature intestine but selectively reduced in surgical necrotizing enterocolitis. PloS One (2014) 9(6):e99042. doi: 10.1371/journal.pone.0099042
40
BrutkiewiczRR. CD1d ligands: the good, the bad, and the ugly. J Immunol (2006) 177(2):769–75. doi: 10.4049/jimmunol.177.2.769
41
CorbettAJAwadWWangHChenZ. Antigen recognition by MR1-reactive T cells; MAIT cells, metabolites, and remaining mysteries. Front Immunol (2020) 11:1961. doi: 10.3389/fimmu.2020.01961
42
GibbonsDLHaqueSFSilberzahnTHamiltonKLangfordCEllisPet al. Neonates harbour highly active gammadelta T cells with selective impairments in preterm infants. Eur J Immunol (2009) 39(7):1794–806. doi: 10.1002/eji.200939222
43
LeeansyahELohLNixonDFSandbergJK. Acquisition of innate-like microbial reactivity in mucosal tissues during human fetal MAIT-cell development. Nat Commun (2014) 5:3143. doi: 10.1038/ncomms4143
44
LohLIvarssonMAMichaëlssonJSandbergJKNixonDF. Invariant natural killer T cells developing in the human fetus accumulate and mature in the small intestine. Mucosal Immunol (2014) 7(5):1233–43. doi: 10.1038/mi.2014.13
45
SwiebodaDRiceTFGuoYNadelSThwaitesRSOpenshawPJMet al. Natural killer cells and innate lymphoid cells but not NKT cells are mature in their cytokine production at birth. Clin Exp Immunol ((2024)) 215(1):1–14. doi: 10.1093/cei/uxad094
46
HarnerSNoessnerENadasKLeumann-RungeASchiemannMFaberFLet al. Cord blood Valpha24-Vbeta11 natural killer T cells display a Th2-chemokine receptor profile and cytokine responses. PloS One (2011) 6(1):e15714. doi: 10.1371/journal.pone.0015714
47
KadowakiNAntonenkoSHoSRissoanMCSoumelisVPorcelliSAet al. Distinct cytokine profiles of neonatal natural killer T cells after expansion with subsets of dendritic cells. J Exp Med (2001) 193(10):1221–6. doi: 10.1084/jem.193.10.1221
48
WeitkampJHKoyamaTRockMTCorreaHGoettelJAMattaPet al. Necrotising enterocolitis is characterised by disrupted immune regulation and diminished mucosal regulatory (FOXP3)/effector (CD4, CD8) T cell ratios. Gut. (2013) 62(1):73–82. doi: 10.1136/gutjnl-2011-301551
49
TianJYanCJiangYZhouHLiLShenJet al. Peripheral and intestinal mucosal-associated invariant T cells in premature infants with necrotizing enterocolitis. Front Pharmacol (2022) 13:1008080. doi: 10.3389/fphar.2022.1008080
50
SproatTPayneRPEmbletonNDBerringtonJHambletonS. T cells in preterm infants and the influence of milk diet. Front Immunol (2020) 11:1035. doi: 10.3389/fimmu.2020.01035
51
TreinerELantzO. CD1d- and MR1-restricted invariant T cells: of mice and men. Curr Opin Immunol (2006) 18(5):519–26. doi: 10.1016/j.coi.2006.07.001
52
Rahman QaziKJensenGBvan der HeidenMBjorkanderSMarchiniGJenmalmMCet al. Extreme prematurity and sepsis strongly influence frequencies and functional characteristics of circulating gammadelta T and natural killer cells. Clin Transl Immunol (2021) 10(6):e1294. doi: 10.1002/cti2.1294
53
KoayHFGherardinNAEndersALohLMackayLKAlmeidaCFet al. A three-stage intrathymic development pathway for the mucosal-associated invariant T cell lineage. Nat Immunol (2016) 17(11):1300–11. doi: 10.1038/ni.3565
54
KovalovskyDUcheOUEladadSHobbsRMYiWAlonzoEet al. The BTB-zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions. Nat Immunol (2008) 9(9):1055–64. doi: 10.1038/ni.1641
55
LuYCaoXZhangXKovalovskyD. PLZF controls the development of fetal-derived IL-17+Vgamma6+ gammadelta T cells. J Immunol (2015) 195(9):4273–81. doi: 10.4049/jimmunol.1500939
56
SalouMLegouxFGiletJDarboisAdu HalgouetAAlonsoRet al. A common transcriptomic program acquired in the thymus defines tissue residency of MAIT and NKT subsets. J Exp Med (2019) 216(1):133–51. doi: 10.1084/jem.20181483
57
Gutierrez-ArcelusMTeslovichNMolaARPolidoroRBNathanAKimHet al. Lymphocyte innateness defined by transcriptional states reflects a balance between proliferation and effector functions. Nat Commun (2019) 10(1):687. doi: 10.1038/s41467-019-08604-4
58
ConstantinidesMGBelkaidY. Early-life imprinting of unconventional T cells and tissue homeostasis. Science (2021) 374(6573):eabf0095. doi: 10.1126/science.abf0095
59
CardellSTangriSChanSKronenbergMBenoistCMathisD. CD1-restricted CD4+ T cells in major histocompatibility complex class II-deficient mice. J Exp Med (1995) 182(4):993–1004. doi: 10.1084/jem.182.4.993
60
ChenYHChiuNMMandalMWangNWangCR. Impaired NK1+ T cell development and early IL-4 production in CD1-deficient mice. Immunity. (1997) 6(4):459–67. doi: 10.1016/S1074-7613(00)80289-7
61
BendelacALantzOQuimbyMEYewdellJWBenninkJRBrutkiewiczRR. CD1 recognition by mouse NK1+ T lymphocytes. Science. (1995) 268:863–5. doi: 10.1126/science.7538697
62
MendirattaSKMartinWDHongSBoesteanuAJoyceSVan KaerL. CD1d1 mutant mice are deficient in natural T cells that promptly produce IL-4. Immunity. (1997) 6(4):469–77. doi: 10.1016/S1074-7613(00)80290-3
63
MoritaMMotokiKAkimotoKNatoriTSakaiTSawaEet al. Structure-activity relationship of alpha-galactosylceramides against B16-bearing mice. J Med Chem (1995) 38(12):2176–87. doi: 10.1021/jm00012a018
64
KawanoTCuiJKoezukaYTouraIKanekoYMotokiKet al. CD1d-restricted and TCR-mediated activation of Va14 NKT cells by glycosylceramides. Science. (1997) 278(5343):1626–9. doi: 10.1126/science.278.5343.1626
65
ZhouDMattnerJCantuC3rdSchrantzNYinNGaoYet al. Lysosomal glycosphingolipid recognition by NKT cells. Science. (2004) 306(5702):1786–9. doi: 10.1126/science.1103440
66
BlomqvistMRhostSTenebergSLofbomLOsterbyeTBriglMet al. Multiple tissue-specific isoforms of sulfatide activate CD1d-restricted type II NKT cells. Eur J Immunol (2009) 39(7):1726–35. doi: 10.1002/eji.200839001
67
WuLVan KaerL. Natural killer T cells in health and disease. Front Biosci (Schol Ed). (2011) 3(1):236–51. doi: 10.2741/s148
68
WuXLiuJLiWKhanMFDaiHTianJet al. CD1d-dependent neuroinflammation impairs tissue repair and functional recovery following a spinal cord injury. bioRxiv (2023). doi: 10.1101/2023.10.13.562047
69
LiuJRenukaradhyaGJBrutkiewiczRR. The Regulation of CD1d+ and CD1d- Tumors by NKT Cells: The roles of NKT cells in regulating CD1d+ and CD1d- tumor immunity. In: TerabeMBerzofskyJA, editors. Natural killer T cells: balancing the regulation of tumor immunity. New York: Springer Science+Business Media, LLC (2011). p. 71–94.
70
LiuJGalloRMKhanMARenukaradhyaGJBrutkiewiczRR. Neurofibromin 1 impairs natural killer T-cell-dependent antitumor immunity against a T-cell lymphoma. Front Immunol (1901) 2018:8. doi: 10.3389/fimmu.2017.01901
71
CuiYWanQ. NKT cells in neurological diseases. Front Cell Neurosci (2019) 13:245. doi: 10.3389/fncel.2019.00245
72
JeongDWooYDChungDH. Invariant natural killer T cells in lung diseases. Exp Mol Med (2023) 55(9):1885–94. doi: 10.1038/s12276-023-01024-x
73
MiyakeSYamamuraT. NKT cells and autoimmune diseases: unraveling the complexity. In: MoodyDB, editor. T cell activation by CD1 and lipid antigens, current topics in microbiology and immunology. Berlin, Heidelberg: Springer (2007).
74
HadilooKTahmasebiSEsmaeilzadehA. CAR-NKT cell therapy: a new promising paradigm of cancer immunotherapy. Cancer Cell Int (2023) 23(1):86. doi: 10.1186/s12935-023-02923-9
75
AhmadiAFallah VastaniZAbounooriMAziziMLabani-MotlaghAMamiSet al. The role of NK and NKT cells in the pathogenesis and improvement of multiple sclerosis following disease-modifying therapies. Health Sci Rep (2022) 5(1):e489. doi: 10.1002/hsr2.489
76
HeczeyACourtneyANMontalbanoARobinsonSLiuKLiMet al. Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma: an interim analysis. Nat Med (2020) 26(11):1686–90. doi: 10.1038/s41591-020-1074-2
77
ComanTRossignolJD'AveniMFabianiBDussiotMRignaultRet al. Human CD4- invariant NKT lymphocytes regulate graft versus host disease. Oncoimmunology. (2018) 7(11):e1470735. doi: 10.1080/2162402X.2018.1470735
78
PrabhuSBRathoreDKNairDChaudharyARazaSKanodiaPet al. Comparison of human neonatal and adult blood leukocyte subset composition phenotypes. PloS One (2016) 11(9):e0162242. doi: 10.1371/journal.pone.0162242
79
HuangSMartinEKimSYuLSoudaisCFremontDHet al. MR1 antigen presentation to mucosal-associated invariant T cells was highly conserved in evolution. Proc Natl Acad Sci U S A. (2009) 106(20):8290–5. doi: 10.1073/pnas.0903196106
80
CorbettAJEckleSBBirkinshawRWLiuLPatelOMahonyJet al. T-cell activation by transitory neo-antigens derived from distinct microbial pathways. Nature. (2014) 509(7500):361–5. doi: 10.1038/nature13160
81
GodfreyDIKoayHFMcCluskeyJGherardinNA. The biology and functional importance of MAIT cells. Nat Immunol (2019) 20(9):1110–28. doi: 10.1038/s41590-019-0444-8
82
NelIBertrandLToubalALehuenA. MAIT cells, guardians of skin and mucosa? Mucosal Immunol (2021) 14(4):803–14. doi: 10.1038/s41385-021-00391-w
83
ToubalALehuenA. Role of MAIT cells in metabolic diseases. Mol Immunol (2021) 130:142–7. doi: 10.1016/j.molimm.2020.12.014
84
KubicaPLara-VelazquezMBamMSirajSOngILiuPet al. MR1 overexpression correlates with poor clinical prognosis in glioma patients. Neurooncol Adv (2021) 3(1):vdab034. doi: 10.1093/noajnl/vdab034
85
SerriariNEEocheMLamotteLLionJFumeryMMarceloPet al. Innate mucosal-associated invariant T (MAIT) cells are activated in inflammatory bowel diseases. Clin Exp Immunol (2014) 176(2):266–74. doi: 10.1111/cei.12277
86
ConstantinidesMGLinkVMTamoutounourSWongACPerez-ChaparroPJHanSJet al. MAIT cells are imprinted by the microbiota in early life and promote tissue repair. Science (2019) 366(6464):eaax6624. doi: 10.1126/science.aax6624
87
MagalhaesIPingrisKPoitouCBessolesSVenteclefNKiafBet al. Mucosal-associated invariant T cell alterations in obese and type 2 diabetic patients. J Clin Invest. (2015) 125(4):1752–62. doi: 10.1172/JCI78941
88
LiuJNanHBrutkiewiczRRCasasnovasJKuaKL. Sex discrepancy in the reduction of mucosal-associated invariant T cells caused by obesity. Immun Inflammation Dis (2021) 9(1):299–309. doi: 10.1002/iid3.393
89
EberhardJMHartjenPKummerSSchmidtREBockhornMLehmannCet al. CD161+ MAIT cells are severely reduced in peripheral blood and lymph nodes of HIV-infected individuals independently of disease progression. PloS One (2014) 9(11):e111323. doi: 10.1371/journal.pone.0111323
90
KonumaTKoharaCWatanabeETakahashiSOzawaGSuzukiKet al. Reconstitution of circulating mucosal-associated invariant T cells after allogeneic hematopoietic cell transplantation: its association with the riboflavin synthetic pathway of gut microbiota in cord blood transplant recipients. J Immunol (2020) 204(6):1462–73. doi: 10.4049/jimmunol.1900681
91
ReantragoonRCorbettAJSakalaIGGherardinNAFurnessJBChenZet al. Antigen-loaded MR1 tetramers define T cell receptor heterogeneity in mucosal-associated invariant T cells. J Exp Med (2013) 210(11):2305–20. doi: 10.1084/jem.20130958
92
RahimpourAKoayHFEndersAClanchyREckleSBMeehanBet al. Identification of phenotypically and functionally heterogeneous mouse mucosal-associated invariant T cells using MR1 tetramers. J Exp Med (2015) 212(7):1095–108. doi: 10.1084/jem.20142110
93
SakalaIGKjer-NielsenLEickhoffCSWangXBlazevicALiuLet al. Functional heterogeneity and antimycobacterial effects of mouse mucosal-associated invariant T cells specific for riboflavin metabolites. J Immunol (2015) 195(2):587–601. doi: 10.4049/jimmunol.1402545
94
WillcoxCRPitardVNetzerSCouziLSalimMSilberzahnTet al. Cytomegalovirus and tumor stress surveillance by binding of a human gammadelta T cell antigen receptor to endothelial protein C receptor. Nat Immunol (2012) 13(9):872–9. doi: 10.1038/ni.2394
95
ZengXWeiYLHuangJNewellEWYuHKiddBAet al. gammadelta T cells recognize a microbial encoded B cell antigen to initiate a rapid antigen-specific interleukin-17 response. Immunity. (2012) 37(3):524–34. doi: 10.1016/j.immuni.2012.06.011
96
RibotJCLopesNSilva-SantosB. gammadelta T cells in tissue physiology and surveillance. Nat Rev Immunol (2021) 21(4):221–32. doi: 10.1038/s41577-020-00452-4
97
ChenYChouKFuchsEHavranWLBoismenuR. Protection of the intestinal mucosa by intraepithelial gamma delta T cells. Proc Natl Acad Sci U S A. (2002) 99(22):14338–43. doi: 10.1073/pnas.212290499
98
RezendeRMCoxLMMoreiraTGLiuSBoulenouarSDhangFet al. Gamma-delta T cells modulate the microbiota and fecal micro-RNAs to maintain mucosal tolerance. Microbiome. (2023) 11(1):32. doi: 10.1186/s40168-023-01478-1
99
BandeiraAMota-SantosTItoharaSDegermannSHeusserCTonegawaSet al. Localization of gamma/delta T cells to the intestinal epithelium is independent of normal microbial colonization. J Exp Med (1990) 172(1):239–44. doi: 10.1084/jem.172.1.239
100
HenrickBMRodriguezLLakshmikanthTPouCHenckelEArzoomandAet al. Bifidobacteria-mediated immune system imprinting early in life. Cell. (2021) 184(15):3884–98e11. doi: 10.1016/j.cell.2021.05.030
101
La RosaPSWarnerBBZhouYWeinstockGMSodergrenEHall-MooreCMet al. Patterned progression of bacterial populations in the premature infant gut. Proc Natl Acad Sci U S A. (2014) 111(34):12522–7. doi: 10.1073/pnas.1409497111
102
ThanertRKeenECDantasGWarnerBBTarrPI. Necrotizing enterocolitis and the microbiome: current status and future directions. J Infect Dis (2021) 223(12 Suppl 2):S257–S63. doi: 10.1093/infdis/jiaa604
103
TremblayÉThibaultMPFerrettiEBabakissaCBertelleVBettolliMet al. Gene expression profiling in necrotizing enterocolitis reveals pathways common to those reported in Crohn's disease. BMC Med Genomics (2016) 9:6. doi: 10.1186/s12920-016-0166-9
104
EgoziAOlaloyeOWernerLSilvaTMcCourtBPierceRWet al. Single cell atlas of the neonatal small intestine with necrotizing enterocolitis. bioRxiv. (2022) 2022:03.01.482508. doi: 10.2139/ssrn.4032068
105
OlaloyeOOLiuPToothakerJMMcCourtBTMcCourtCCXiaoJet al. CD16+CD163+ monocytes traffic to sites of inflammation during necrotizing enterocolitis in premature infants. J Exp Med (2021) 218(9):e20200344. doi: 10.1084/jem.20200344
106
EgoziAOlaloyeOWernerLSilvaTMcCourtBPierceRWet al. Single-cell atlas of the human neonatal small intestine affected by necrotizing enterocolitis. PloS Biol (2023) 21(5):e3002124. doi: 10.1371/journal.pbio.3002124
107
WingenderGStepniakDKrebsPLinLMcBrideSWeiBet al. Intestinal microbes affect phenotypes and functions of invariant natural killer T cells in mice. Gastroenterology. (2012) 143(2):418–28. doi: 10.1053/j.gastro.2012.04.017
108
OlszakTAnDZeissigSVeraMPRichterJFrankeAet al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science. (2012) 336(6080):489–93. doi: 10.1126/science.1219328
109
TabilasCIuDSDalyCWPYee MonKJReynaldiAWesnakSPet al. Early microbial exposure shapes adult immunity by altering CD8+ T cell development. Proc Natl Acad Sci U S A. (2022) 119(49):e2212548119. doi: 10.1073/pnas.2212548119
110
DiasJBoulouisCGorinJBvan den BiggelaarRLalKGGibbsAet al. The CD4(-)CD8(-) MAIT cell subpopulation is a functionally distinct subset developmentally related to the main CD8(+) MAIT cell pool. Proc Natl Acad Sci U S A. (2018) 115(49):E11513–E22. doi: 10.1073/pnas.1812273115
111
Van KaerLAlgoodHMSSinghKParekhVVGreerMJPiazueloMBet al. CD8alphaalpha(+) innate-type lymphocytes in the intestinal epithelium mediate mucosal immunity. Immunity. (2014) 41(3):451–64. doi: 10.1016/j.immuni.2014.08.010
112
LiuJHunterCManoharKMesfinFShelleyWCBrokawJet al. MR1-deficiency in neonatal mice renders protection from necrotizing enterocolitis. J Immunol (2023) 210(1_Supplement):66.16–6. doi: 10.4049/jimmunol.210.Supp.66.16
113
BharadwajNSGumperzJE. Harnessing invariant natural killer T cells to control pathological inflammation. Front Immunol (2022) 13:998378. doi: 10.3389/fimmu.2022.998378
114
KappJAKappLMMcKennaKC. Gammadelta T cells play an essential role in several forms of tolerance. Immunol Res (2004) 29(1-3):93–102. doi: 10.1385/IR:29:1-3:093
115
GiriSLalG. Differentiation and functional plasticity of gamma-delta (γδ) T cells under homeostatic and disease conditions. Mol Immunol (2021) 136:138–49. doi: 10.1016/j.molimm.2021.06.006
116
GiriSMeiteiHTMishraALalG. Vγ2(+) γδ T cells in the presence of anti-CD40L control surgical inflammation and promote skin allograft survival. J Invest Dermatol (2022) 142(10):2706–14.e3. doi: 10.1016/j.jid.2022.03.016
117
EganCESodhiCPGoodMLinJJiaHYamaguchiYet al. Toll-like receptor 4-mediated lymphocyte influx induces neonatal necrotizing enterocolitis. J Clin Invest. (2016) 126(2):495–508. doi: 10.1172/JCI83356
118
Ness-SchwickerathKJMoritaCT. Regulation and function of IL-17A- and IL-22-producing gammadelta T cells. Cell Mol Life Sci (2011) 68(14):2371–90. doi: 10.1007/s00018-011-0700-z
119
LeeYJHolzapfelKLZhuJJamesonSCHogquistKA. Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells. Nat Immunol (2013) 14(11):1146–54. doi: 10.1038/ni.2731
120
ParkKJJinHMChoYNYoonJHKeeSJKimHSet al. Altered frequency, activation, and clinical relevance of circulating innate and innate-like lymphocytes in patients with alcoholic liver cirrhosis. Immune Netw (2023) 23(3):e22. doi: 10.4110/in.2023.23.e22
121
DeshpandeGRaoSPatoleSBulsaraM. Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates. Pediatrics. (2010) 125(5):921–30. doi: 10.1542/peds.2009-1301
122
AlFalehKAnabreesJ. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev (2022) PUB4:CD005496. doi: 10.1002/14651858.CD005496.pub4
123
PatelRMUnderwoodMA. Probiotics and necrotizing enterocolitis. Semin Pediatr Surg (2018) 27(1):39–46. doi: 10.1053/j.sempedsurg.2017.11.008
124
GodfreyDILe NoursJAndrewsDMUldrichAPRossjohnJ. Unconventional T cell targets for cancer immunotherapy. Immunity. (2018) 48(3):453–73. doi: 10.1016/j.immuni.2018.03.009
125
HuangS. Targeting innate-like T cells in tuberculosis. Front Immunol (2016) 7:594. doi: 10.3389/fimmu.2016.00594
126
HuangWHeWShiXHeXDouLGaoY. The role of CD1d and MR1 restricted T cells in the liver. Front Immunol (2018) 9:2424. doi: 10.3389/fimmu.2018.02424
127
StolkDvan der VlietHJde GruijlTDvan KooykYExleyMA. Positive & Negative roles of innate effector cells in controlling cancer progression. Front Immunol (2018) 9:1990. doi: 10.3389/fimmu.2018.01990
128
MihiBGongQNolanLSGaleSEGoreeMHuEet al. Interleukin-22 signaling attenuates necrotizing enterocolitis by promoting epithelial cell regeneration. Cell Rep Med (2021) 2(6):100320. doi: 10.1016/j.xcrm.2021.100320
129
MakkoukAYangXCBarcaTLucasATurkozMWongJTSet al. Off-the-shelf Vδ1 gamma delta T cells engineered with glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust antitumor efficacy against hepatocellular carcinoma. J Immunother Cancer (2021) 9(12):e003441. doi: 10.1136/jitc-2021-003441
130
BohineustATourretMDerivryLCaillat-ZucmanS. Mucosal-associated invariant T (MAIT) cells, a new source of universal immune cells for chimeric antigen receptor (CAR)-cell therapy. Bull Cancer (2021) 108(10s):S92–s5. doi: 10.1016/j.bulcan.2021.07.003
131
StadtmauerEAFraiettaJADavisMMCohenADWeberKLLancasterEet al. CRISPR-engineered T cells in patients with refractory cancer. Science (2020) 367(6481):eaba7365. doi: 10.1126/science.aba7365
132
LiuJBrutkiewiczRR. The Toll-like receptor 9 signalling pathway regulates MR1-mediated bacterial antigen presentation in B cells. Immunology. (2017) 152(2):232–42. doi: 10.1111/imm.12759
133
TengMWSharkeyJMcLaughlinNMExleyMASmythMJ. CD1d-based combination therapy eradicates established tumors in mice. J Immunol (2009) 183(3):1911–20. doi: 10.4049/jimmunol.0900796
134
TazawaHIreiTTanakaYIgarashiYTashiroHOhdanH. Blockade of invariant TCR-CD1d interaction specifically inhibits antibody production against blood group A carbohydrates. Blood. (2013) 122(15):2582–90. doi: 10.1182/blood-2012-02-407452
135
SampathVMartinezMCaplanMUnderwoodMACunaA. Necrotizing enterocolitis in premature infants-A defect in the brakes? Evidence from clinical and animal studies. Mucosal Immunol (2023) 16(2):208–20. doi: 10.1016/j.mucimm.2023.02.002
Summary
Keywords
immunity, innate T cells, NKT, MAIT, γδ T, neonates, preterm, necrotizing enterocolitis
Citation
Liu J, Joseph S, Manohar K, Lee J, Brokaw JP, Shelley WC and Markel TA (2024) Role of innate T cells in necrotizing enterocolitis. Front. Immunol. 15:1357483. doi: 10.3389/fimmu.2024.1357483
Received
18 December 2023
Accepted
16 January 2024
Published
08 February 2024
Volume
15 - 2024
Edited by
Luc Van Kaer, Vanderbilt University Medical Center, United States
Reviewed by
Danyvid Olivares-Villagómez, Vanderbilt University Medical Center, United States
Guan Yang, City University of Hong Kong, Hong Kong SAR, China
Updates
Copyright
© 2024 Liu, Joseph, Manohar, Lee, Brokaw, Shelley and Markel.
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) and the copyright owner(s) 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: Jianyun Liu, jealiu@iu.edu
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.