that are enriched for riboflavin synthesis genes
( 4 ), are enriched during the last trimester of
pregnancy in humans and colonize both hu-
man and mouse neonates from birth ( 25 – 28 ),
leading to an abundance of MAIT cell antigens
during early-life development.
Additional microbial metabolites may also
regulate the development of MAIT cells be-
cause MR1 has also been shown to present
antigens that do not derive from riboflavin
biosynthesis ( 29 , 30 ). Because MAIT cells
have recently been shown to contribute to
both tissue repair and antimicrobial immu-
nity ( 4 , 31 – 34 ), the microbial imprinting of
MAIT cell frequency in early life would be
expected to have long-term implications for
tissue homeostasis.
Although the vast majority of unconven-
tional T cells are tissue-resident, some sub-
sets can acquire migratory capabilities under
defined settings—a property that may enable
these cells to mediate the distal and long-term
impact of the microbiota. For instance, broad-
spectrum antibiotic treatment during the neo-
natal period has been shown to increase the
severity of experimentally induced psoriasis
in adult mice due to persistent intestinal dys-
biosis ( 35 ). The resulting loss of microbial
diversity corresponds with an increase in the
frequency of interleukin-22 (IL-22)–producing
Vg 4 +gdT cells within the skin [Heilig and
Tonegawa nomenclature ( 36 )], which is nec-
essary for disease pathology ( 35 ). Conversely,
antibiotic treatment of adult animals amelio-
rates psoriasis and reduces the frequency of
IL-22+Vg 4 +gdT cells ( 35 ), supporting the
idea that the early-life microbiota is uniquely
susceptible to external perturbations that can
imprint long-term microbial dysbiosis and
promote proinflammatory unconventional
T cells. More generally, both experimental
and clinical observations support the idea that
early-life alterations in microbiota can have a
detrimental impact on the host ( 37 ). However,
the extent to which maladapted early inter-
actions between unconventional T cells and
the microbiota predispose to disease remains
an open question.
In addition to early-life microbial signals
that regulate unconventional T cells, expression
of host molecules during defined developmen-
tal periods can shape local T cell populations.
Within barrier tissues in particular, epithe-
lial cells have been shown to provide early
instructive signals for defined subsets of un-
conventional T cells. For instance, epithelial
cells display butyrophilin-like (Btnl) molecules
such as Btnl1 that induce TCR-dependent
stimulation of intraepithelial lymphocyte (IEL)
gdT cells ( 38 ). Although the induction of Btnl1
on enterocytes is sufficient to expand the in-
testinal Vg 7 +IEL population, expression of
Btnl1 after 7 weeks of age does not alter their
abundance ( 38 ), demonstrating an early-life
window for epithelial cell imprinting of un-
conventional T cells. Despite the abundance
of unconventional T cells within barrier tis-
sues, much remains to be understood about
the role of epithelial and stromal cells in pro-
viding early-life instructive signals.Competition between unconventional T cells:
A cellular network
Unconventional T cells have been often ex-
plored one subset at a time, but recent evi-
dence supports the idea that these cells should
be assessed as a network of cells with poten-
tially overlapping and/or redundant functions.
Indeed, although unconventional T cells re-
spond to disparate antigens, they express
remarkably similar transcriptional programs
( 39 ),resultinginaninherentcompetitionthat
results in the maintenance of a relatively stable
level of effector cells within tissues.
The ability of unconventional T cells to
compete for defined niches has been shown
in various tissues. For instance, mice defi-
cient in microRNAs miR-181a and miR-181b
exhibit a severe reduction of iNKT cells and
a corresponding increase of NK1.1+gdT cells
in the liver ( 40 ), where iNKT cells represent
a substantial population. Although iNKT cells
are nearly absent from all organs in these ani-
mals ( 41 ), the compensatory expansion ofgd
T cells does not occur in the thymus or lymph
nodes ( 40 ), which suggests that this interplay
between unconventional T cells may only
occur in tissues where they are abundant. Ad-
ditionally, hepatic NK1.1+gdT cells express
type 1 markers, including the IL-12 receptor
and interferon-g(IFN-g)( 42 ), whereas the pre-
dominant iNKT subset within the liver is the
type 1 iNKT1 population ( 9 ). Thus, these pop-
ulationslikelycompeteforthesametrophicor
survival factors, leading to an inverse correla-
tion between them. In the dermis, wheregd
T cells are the predominant type 17 effector cells
in mice, both MAIT cells and iNKT cells are
increased inTcrd–/–animals ( 4 ). However, cuta-
neous MAIT cells andgdT cells are unaffected
by the lack of iNKT cells in CD1d-deficient mice
( 4 ), likely because of the comparatively low
number of iNKT cells in the skin. By contrast,
in the thymus, spleen, and liver, where iNKT
cells account for a large proportion of effector
T cells,Cd1d–/–mice show a compensatory
increase of MAIT cells ( 22 ). The thymic MAIT
cells that expand are at the mature CD44+
developmental stage ( 22 ), which coincides
with the expression either RORgtorT-betand
the associated effector molecules and recep-
tors ( 43 ); these findings support the hypothesis
that the competition between unconventional
Tcellsmaybemediatedbycytokines.Re-
cently, the intrinsic ability of these popula-
tions to compete was confirmed in a patient
harboring a homozygous point mutation in
MR1associated with an absence of MAIT cellsand concomitant expansion ingdT cells ( 44 ).
Experimentally, cytokines such as IL-23 and
IL-1 have been proposed to contribute to this
phenomenon, but for the most part, the nature
of the trophic or survival factors responsible for
the tissue-specific composition and frequen-
cy of unconventional T cells remains poorly
understood (Fig. 3).
Although competition exists among uncon-
ventional T cells, each subset may serve dis-
tinct roles in promoting tissue physiology as
a result of inherent differences in localization.
For example, cutaneous Vg 5 +Vd 1 +dendritic
epidermal T cells (DETCs) are restricted to the
epidermis, whereas Vg 4 +and Vg 6 +gdT cells
reside in the dermis with conventionalab
T cells ( 45 )andMAITcellsarepositioned
below the dermal-epidermal interface ( 4 ),
termed the basement membrane. However,
the signals that regulate the stratification of
unconventional T cells within tissues have not
been established, nor is it known whether this
localization is necessary for their function.
The extent to which the competition among
unconventional T cells contributes to disease
susceptibility has not been established. Indeed,
infection or chronic infection may displace
tissue-resident unconventional T cells, open-
ing the door to an expansion of inappropriate
competitors. For example, a recent study re-
vealed that subsets ofgdT cells can also com-
pete with one another under inflammatory
conditions. The healthy human intestine
contains Vg 4 +Vd 1 +IELs that recognize the
butyrophilin-like molecules BTNL3 and BTNL8
and promote tissue homeostasis though their
cytotoxic and tissue repair programs ( 38 , 46 ).
However, the chronic inflammation caused by
celiac disease abrogates BTNL8 expression on
epithelial cells, resulting in loss of Vg 4 +Vd 1 +
IELs and a corresponding expansion of in-
flammatory Vd 1 +IELs bearing an H-J1 CDR3g
motif and producing more IFN-g( 47 ). Although
the removal of dietary gluten restores BTNL8
expression, it is insufficient to reconstitute
the Vg 4 +Vd 1 +IEL population, indicating that
chronic inflammation can permanently alter
the tissue milieu. To what extent alterations
in the repertoire and frequencies of uncon-
ventional T cells cause predisposition to in-
flammatory states remains to be determined.
The ability of unconventional T cells to com-
pete within tissues may have, in some settings,
hindered our ability to understand the precise
role of individual subsets. This phenomenon
also raises an intriguing hypothesis that the
ability of unconventional T cells to compen-
sate for each other contributes to tissue resil-
ience by preserving essential tissue functions.Tissue repair and maintenance of homeostasis
Although the antimicrobial functions of un-
conventional T cells have been established ( 2 ),
emerging evidence indicates that one of theConstantinides and Belkaid,Science 374 , eabf0095 (2021) 10 December 2021 3of6
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