closure, which was interpreted to indicate
that iNKT cells inhibit tissue repair ( 65 ). How-
ever, the recently described competition among
unconventional T cells could mean that pre-
vention of CD1d-mediated iNKT activation and
accumulation after injury may increase the
abundance of other unconventional T cells that
have been shown to promote wound healing,
including MAIT cells andgdT cells. Thus, it
remains to be determined whether iNKT cells
also participate in tissue repair.
Although T cells that recognizeN-formylated
peptides presented by the MHC-Ib molecule
H2-M3 display a diverse TCR repertoire ( 66 ),
they exhibit innate-like effector characteristics
and have recently been shown to promote tis-
sue repair ( 67 – 69 ). After topical application of
S. epidermidis, H2-M3–restricted RORgt+CD8+
T cells preferentially accumulate in the epider-
mis, where they express immunoregulatory
and tissue repair transcriptional signatures
( 60 , 68 ). The transcriptional program of the
H2-M3–restricted RORgt+CD8+T cells closely
resembles that of MAIT cells after the resolu-
tion of aLegionellainfection, which also dis-
play tissue repair genes ( 31 ). Conversely, after
an inflammatory intradermal inoculation of
S. epidermidis, H2-M3–restricted T-bet+CD8+
T cells result ( 60 , 69 ), which lack the immu-
noregulatory and tissue repair characteristics
of the RORgt+cells ( 68 ). Because homeostatic
interactions with the microbiota are necessary
for the induction of a tissue repair signature
in H2-M3–restricted T cells, robust cytokine-
mediated activation likely induces effector
characteristics analogously to MAIT cells ( 32 ).
After a cutaneous injury, H2-M3–restricted
RORgt+CD8+T cells accumulate at the wound
edge, where damage-associated alarmins, and
in particular IL-18, promote their production
of type 2 cytokines, which contribute to the
re-epithelialization of the wound and thus
restore tissue homeostasis ( 68 , 69 ).
Growing evidence indicates that the role of
unconventional T cells is highly dependent on
their tissue localization, host developmental
stage, and disease context. Indeed, although
the ability of unconventional T cells to promote
epithelial growth and angiogenesis is beneficial
in the context of tissue repair, these functions
can also exacerbate tumorigenesis. For in-
stance, the production of IL-17 by lung-resident
Vg 6 +Vd 1 +T cells in response to the local mi-
crobiota promotes neutrophil infiltration into
lung adenocarcinomas and increases tumor
development ( 70 ). Conversely,gdT cells and
other unconventional T cells also exhibit anti-
tumor responses ( 71 ). MAIT cells were recently
shown to target myeloma cells pulsed with
the riboflavin derivative 5-OP-RU, and an
MR1-restricted T cell clone from human pe-
ripheral blood was found to kill a broad range
of cancer cells ( 72 , 73 ). Microbiota-mediated
conversion of bile acids regulates the accumu-
lation of iNKT cells in the liver, which inhibit
hepatic tumor growth ( 74 ). Furthermore, un-
conventional T cells make attractive targets
for chimeric antigen receptor T cell therapy
because their restriction by monomorphic
MHC-Ib molecules avoids the possibility of
graft-versus-host disease ( 71 ).
Because of the complexity and interrelated
functions of unconventional T cells, this evo-
lutionarily ancient arm of the immune system
is expected to contribute extensively to the
control of both host physiology and disease
states. As such, leveraging the ability of these
tissue-resident cells to rapidly respond to ca-
nonical antigens, alarmins, and/or common
survival factors may represent an important
and highly physiological therapeutic strategy.REFERENCESANDNOTES- L. C. Rankin, D. Artis, Beyond Host Defense: Emerging
Functions of the Immune System in Regulating Complex Tissue
Physiology.Cell 173 , 554–567 (2018). doi:10.1016/
j.cell.2018.03.013; pmid: 29677509 - D. I. Godfrey, A. P. Uldrich, J. McCluskey, J. Rossjohn,
D. B. Moody, The burgeoning family of unconventional T cells.
Nat. Immunol. 16 , 1114–1123 (2015). doi:10.1038/ni.3298;
pmid: 26482978 - D. Anet al., Sphingolipids from a symbiotic microbe regulate
homeostasis of host intestinal natural killer T cells.Cell 156 ,
123 – 133 (2014). doi:10.1016/j.cell.2013.11.042; pmid: 24439373 - M. G. Constantinideset al., MAIT cells are imprinted by the
microbiota in early life and promote tissue repair.Science 366 ,
eaax6624 (2019). doi:10.1126/science.aax6624;
pmid: 31649166 - E. Leeansyah, L. Loh, D. F. Nixon, J. K. Sandberg, Acquisition of
innate-like microbial reactivity in mucosal tissues during
human fetal MAIT-cell development.Nat. Commun. 5 , 3143
(2014). doi:10.1038/ncomms4143; pmid: 24452018 - J. D. Haaset al., Development of interleukin-17-producinggd
T cells is restricted to a functional embryonic wave.Immunity
37 , 48–59 (2012). doi:10.1016/j.immuni.2012.06.003;
pmid: 22770884 - K. Narayanet al., Intrathymic programming of effector fates in
three molecularly distinctgdT cell subtypes.Nat. Immunol. 13 ,
511 – 518 (2012). doi:10.1038/ni.2247; pmid: 22473038 - P. Tieppoet al., The human fetal thymus generates invariant
effectorgdT cells.J. Exp. Med. 217 , e20190580 (2020).
doi:10.1084/jem.20190580; pmid: 31816633 - M. G. Constantinides, A. Bendelac, Transcriptional regulation of
the NKT cell lineage.Curr. Opin. Immunol. 25 , 161–167 (2013).
doi:10.1016/j.coi.2013.01.003; pmid: 23402834 - A. Bendelac, P. B. Savage, L. Teyton, The biology of NKT cells.
Annu. Rev. Immunol. 25 , 297–336 (2007). doi:10.1146/
annurev.immunol.25.022106.141711; pmid: 17150027 - B. Weiet al., Commensal microbiota and CD8+ T cells shape
the formation of invariant NKT cells.J. Immunol. 184 ,
1218 – 1226 (2010). doi:10.4049/jimmunol.0902620;
pmid: 20048124 - G. Wingenderet al., Intestinal microbes affect phenotypes and
functions of invariant natural killer T cells in mice.
Gastroenterology 143 , 418–428 (2012). doi:10.1053/
j.gastro.2012.04.017; pmid: 22522092 - T. Olszaket al., Microbial exposure during early life has
persistent effects on natural killer T cell function.Science 336 ,
489 – 493 (2012). doi:10.1126/science.1219328;
pmid: 22442383 - M. G. Constantinides, B. D. McDonald, P. A. Verhoef,
A. Bendelac, A committed precursor to innate lymphoid cells.
Nature 508 , 397–401 (2014). doi:10.1038/nature13047;
pmid: 24509713 - A. K. Savageet al., The transcription factor PLZF directs the
effector program of the NKT cell lineage.Immunity 29 ,
391 – 403 (2008). doi:10.1016/j.immuni.2008.07.011;
pmid: 18703361 - M. Ennamoratiet al., Intestinal microbes influence
development of thymic lymphocytes in early life.Proc. Natl.
Acad. Sci. U.S.A. 117 , 2570–2578 (2020). doi:10.1073/
pnas.1915047117; pmid: 31964813
17. M. G. Constantinides, Interactions between the microbiota and
innate and innate-like lymphocytes.J. Leukoc. Biol. 103 ,
409 – 419 (2018). doi:10.1002/JLB.3RI0917-378R;
pmid: 29345366
18. L. Le Bourhiset al., Antimicrobial activity of mucosal-
associated invariant T cells.Nat. Immunol. 11 , 701–708 (2010).
doi:10.1038/ni.1890; pmid: 20581831
19. G. Ben Youssefet al., Ontogeny of human mucosal-associated
invariant T cells and related T cell subsets.J. Exp. Med.
215 , 459–479 (2018). doi:10.1084/jem.20171739;
pmid: 29339446
20. P. Chenet al., Circulating Mucosal-Associated Invariant T Cells
in a Large Cohort of Healthy Chinese Individuals From
Newborn to Elderly.Front. Immunol. 10 , 260 (2019).
doi:10.3389/fimmu.2019.00260; pmid: 30838000
21. F. Legouxet al., Microbial metabolites control the thymic
development of mucosal-associated invariant T cells.Science
366 , 494–499 (2019). doi:10.1126/science.aaw2719;
pmid: 31467190
22. H. F. Koayet al., A three-stage intrathymic development
pathway for the mucosal-associated invariant T cell lineage.
Nat. Immunol. 17 , 1300–1311 (2016). doi:10.1038/ni.3565;
pmid: 27668799
23. E. Treineret al., Selection of evolutionarily conserved mucosal-
associated invariant T cells by MR1.Nature 422 , 164– 169
(2003). doi:10.1038/nature01433; pmid: 12634786
24. M. G. Rooks, W. S. Garrett, Gut microbiota, metabolites and
host immunity.Nat. Rev. Immunol. 16 , 341–352 (2016).
doi:10.1038/nri.2016.42; pmid: 27231050
25. M. C. Arrieta, L. T. Stiemsma, N. Amenyogbe, E. M. Brown,
B. Finlay, The intestinal microbiome in early life: Health and
disease.Front. Immunol. 5 , 427 (2014). doi:10.3389/
fimmu.2014.00427; pmid: 25250028
26. J. L. Combellicket al., Differences in the fecal microbiota of
neonates born at home or in the hospital.Sci. Rep. 8 , 15660
(2018). doi:10.1038/s41598-018-33995-7; pmid: 30353125
27. D. M. Chuet al., Maturation of the infant microbiome
community structure and function across multiple body sites
and in relation to mode of delivery.Nat. Med. 23 , 314– 326
(2017). doi:10.1038/nm.4272; pmid: 28112736
28. O. Korenet al., Host remodeling of the gut microbiome and
metabolic changes during pregnancy.Cell 150 , 470– 480
(2012). doi:10.1016/j.cell.2012.07.008; pmid: 22863002
29. M. J. Harriffet al., MR1 displays the microbial metabolome
driving selective MR1-restricted T cell receptor usage.Sci.
Immunol. 3 , eaao2556 (2018). doi:10.1126/sciimmunol.
aao2556; pmid: 30006464
30. A. N. Kelleret al., Drugs and drug-like molecules can modulate
the function of mucosal-associated invariant T cells.Nat.
Immunol. 18 , 402–411 (2017). doi:10.1038/ni.3679;
pmid: 28166217
31. T. S. C. Hinkset al., Activation and In Vivo Evolution of the
MAIT Cell Transcriptome in Mice and Humans Reveals Tissue
Repair Functionality.Cell Rep. 28 , 3249–3262.e5 (2019).
doi:10.1016/j.celrep.2019.07.039; pmid: 31533045
32. T. Lenget al., TCR and Inflammatory Signals Tune Human
MAIT Cells to Exert Specific Tissue Repair and Effector
Functions.Cell Rep. 28 , 3077–3091.e5 (2019). doi:10.1016/
j.celrep.2019.08.050; pmid: 31533032
33. H. Wanget al., MAIT cells protect against pulmonary Legionella
longbeachae infection.Nat. Commun. 9 , 3350 (2018).
doi:10.1038/s41467-018-05202-8; pmid: 30135490
34. B. van Wilgenburget al., MAIT cells contribute to protection
against lethal influenza infection in vivo.Nat. Commun. 9 , 4706
(2018). doi:10.1038/s41467-018-07207-9; pmid: 30413689
35. P. Zanvitet al., Antibiotics in neonatal life increase murine
susceptibility to experimental psoriasis.Nat. Commun. 6 , 8424
(2015). doi:10.1038/ncomms9424; pmid: 26416167
36. J. S. Heilig, S. Tonegawa, Diversity of murineggenes and
expression in fetal and adult T lymphocytes.Nature 322 ,
836 – 840 (1986). doi:10.1038/322836a0; pmid: 2943999
37. S. Tamburini, N. Shen, H. C. Wu, J. C. Clemente, The
microbiome in early life: Implications for health outcomes.
Nat. Med. 22 , 713–722 (2016). doi:10.1038/nm.4142;
pmid: 27387886
38. R. Di Marco Barroset al., Epithelia Use Butyrophilin-like
Molecules to Shape Organ-SpecificgdT Cell Compartments.
Cell 167 , 203–218.e17 (2016). doi:10.1016/j.cell.2016.08.030;
pmid: 27641500
39. M. Gutierrez-Arceluset al., Lymphocyte innateness defined by
transcriptional states reflects a balance between proliferation
and effector functions.Nat. Commun. 10 , 687 (2019).
doi:10.1038/s41467-019-08604-4; pmid: 30737409
Constantinides and Belkaid,Science 374 , eabf0095 (2021) 10 December 2021 5of6
RESEARCH | REVIEW