REVIEW SUMMARY
◥IMMUNOLOGY
Early-life imprinting of unconventional T cells
and tissue homeostasis
Michael G. Constantinidesand Yasmine Belkaid
BACKGROUND:In addition to providing anti-
microbial immunity, the immune system gov-
erns numerous aspects of host physiology, in
part through the coordinated action of tissue-
resident lymphocytes. Although conventional
T cells recognize peptides presented by poly-
morphic major histocompatibility complexes
(MHCs), a large proportion of T cells within
tissues are specific for modified peptides and
small molecules. These unconventional T cells
are restricted by monomorphic MHC mole-
cules, many of which exhibit a high level of
conservation across species, suggesting an
essential role for these cells throughout evo-
lution. Some unconventional T cells express
semi-invariant T cell receptors (TCRs) that
limit their antigenic range analogously to in-
nate immune receptors. Termed innate-like
T cells, these populations developmentally ac-
quire effector characteristics prior to thymic
egress, including rapid cytokine release and ex-
pression of chemokine receptors and integrins.
Without the necessity of antigen-mediated ac-
tivation within secondary lymphoid organs,
innate-like T cells accumulate within tissues
earlier than conventional effector T cells. Con-
sequently, recent work has shown that these
unconventional T cells are particularly re-
sponsive to early-life signals and promote
the maintenance of tissue homeostasis as a
coordinated network.
ADVANCES:As a consequence of their emer-
gence in early life, unconventional T cells
contribute to the initial dialog between the
host and the microbiota, on which some sub-
sets depend for their development. Exposure
to commensal microbes during the first weeks
of life imprints the abundance of mucosal-
associated invariant T (MAIT) cells and in-
variant natural killer T (iNKT) cells in tissues,
due to both TCR-mediated activation and mod-
ulation of tissue-specific chemokines. Epithe-
lial cell expression of host molecules in early
life is also necessary for the accumulation of a
defined subset ofgdT cells. Absence of these
early-life signals cannot be compensated for
later in life and has long-lasting consequences
for host physiology, rendering adult animals
more susceptible to inflammation. Although
the antimicrobial functions of unconventional
T cells have been established, recent work has
demonstrated their contributions to host me-
tabolism, tissue repair, and the maintenance
of homeostasis. In addition to mediating epi-
thelial repair directly via the expression of
growth factors,gdT cells can also promote
tissue homeostasis by inducing the release
of alarmins, which recruit regulatory T cells
and reparative type 2 innate lymphoid cells,
as well as promoting thermoregulation within
adipose tissue. Alarmins also enable a subset
of unconventional CD8+T cells to release type 2
cytokines that promote wound healing. Addi-
tionally, MAIT cells express transcripts asso-
ciated with tissue repair and contribute to
healing, with commensal microbes and their
metabolites enhancing these reparative func-
tions. However, the response of MAIT cellsand other unconventional T cells to micro-
bial exposure is context-dependent, with the
proinflammatory cytokines released during an
infection inducing a distinct transcriptional
profile characterized by effector functions,
accompanied by diminished expression of
tissue repair genes. Although unconventional
T cells exhibit overlapping roles, their disparate
stratification within epithelial tissues suggests
that each population may serve a unique pur-
pose in maintaining tissue homeostasis. Animal
models deficient in subsets of unconventional
T cells exhibit compensatory increases of other
unconventional T cells, indicating that these
populations constitute a network of redundant
cellular mechanisms that contribute to tissue
resilience. However, inflammation can abro-
gate the expression of epithelial molecules
that maintain a subsetgdT cells, resulting in a
compensatory increase in more inflammatory
gdT cells that predispose the tissue to chronic
inflammation.OUTLOOK:Although the causes of competition
between unconventional T cells remain to be
determined, the demonstrated contributions
of these populations to barrier immunity and
tissue homeostasis provide opportunities for
novel therapeutics. Indeed, the abundance of
unconventional T cells from infancy and their
recognition of conserved microbial products
could be exploited to combat early-life infec-
tions, even with the increasing prevalence of
antibiotic resistance. Although the microbial
responsiveness of unconventional T cells may
enable the development of pre/probiotics that
modulate their function and use for the pre-
vention of dysbiosis, the dependence of some
subsets on early-life microbial interactions
suggests that antibiotic use and malnutrition
during this period may impart lifelong conse-
quences for immunity. Furthermore, 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. Therefore,
the development of safe and effective treatments
requires an understanding of the unique in-
tricacies of unconventional T cells. We discuss
the identification of signals responsible for
the development of unconventional T cells and
their accumulation within tissues. Addition-
ally, we examine how alterations in early-life
signals or inflammatory challenges can imprint
the unconventional T cell network and affect
tissue homeostasis for the long term.▪RESEARCH
1338 10 DECEMBER 2021¥VOL 374 ISSUE 6573 science.orgSCIENCE
The list of author affiliations is available in the full article online.
*Corresponding author. Email: [email protected]
(M.G.C.); [email protected] (Y.B.)
Cite this article as M. G. Constantinides and Y. Belkaid,Science
374 , eabf0095 (2021). DOI: 10.1126/science.abf0095READ THE FULL ARTICLE AT
https://doi.org/10.1126/science.abf0095iNKT MAITγδ TEarly lifeAdulthoodRepairMAIT iNKT γδ THomeostasisEarly-life imprinting of unconventional T cells
determines tissue physiology in adulthood.
Unconventional T cells, including invariant natural
killer T (iNKT) cells, mucosal-associated invariant
T (MAIT) cells, andgdT cells, develop in response
to microbial and epithelial signals in early life
and subsequently promote tissue repair and
homeostasis as a coordinated network.