Science - USA (2021-12-10)

dominant functions of these cells may be
associated with the preservation or restora-
tion of tissue homeostasis. Such a property can
be, at least in part, explained by the ability of
unconventional T cells to rapidly respond not
only to defined ligands, but also to alarmins
such as IL-18 or IL-33 that are produced in the
contextoftissuedamage( 48 ).
IntestinalgdIELs and DETCs produce fi-
broblast growth factors, which promote the
proliferation and differentiation of epithelial
cells, returning these tissues to homeostasis
after damage ( 49 , 50 ). Upon injury, epidermal
keratinocytes at the wound edge up-regulate
the expression of butyrophilin-like molecules
encoded bySkintgenes ( 51 ), which are recog-
nized by DETCs in a TCR-dependent manner
( 52 ). Expression ofSkintgenes is diminished
in the skin of aged mice, resulting in fewer
DETCs at the site of the wound relative to
young mice and, consequently, delayed wound
closure ( 51 ). After activation, DETCs in close
proximity to the wound lose their characteris-
tic dendritic morphology and express insulin-
like growth factor 1 (IGF-1), which reduces
keratinocyte apoptosis ( 50 , 53 ). Although both
abandgdT cells from acutely wounded hu-
man tissue express IGF-1, T cells from chronic
wounds do not and are refractory to TCR
stimulation ( 54 ). This suggests that chronic
wounds may persist in part because of the un-
responsiveness of cutaneous T cells.
In addition to mediating epithelial repair
directly via the expression of growth factors,
gdT cells can also promote tissue homeostasis
through the recruitment of regulatory T (Treg)
cells and type 2 innate lymphoid cells (ILC2s).
Influenza infection of neonatal mice results
in the accumulation of CD27–gdT cells that
produce IL-17, which is sufficient to induce
IL-33 expression by lung epithelial cells ( 55 ).

Deficiency in eithergdT cells or IL-33 abro-

gates the accumulation of ILC2s and Tregcells

and their production of amphiregulin, result-

ing in decreased survival after infection ( 55 ).

AlthoughTcrd–/–mice exhibit increased in-

flammation, their viral titers are comparable

to wild-type controls ( 55 ), supporting the idea

thatgdT cells may provide protection to in-

fluenza by promoting tissue repair rather than

enhancing antiviral immunity. Additionally,

PLZF+Vg 6 +gdT cells within adipose tissue

promote the accumulation of ST2+Tregcells

by producing IL-17 and tumor necrosis fac-

tor, which induce IL-33 release from adipose

stromal cells ( 56 ). Because IL-33 promotes

adaptive thermogenesis by inducing expres-

sion of uncoupling protein 1 (UCP1) in brown

and beige adipocytes ( 57 ),gdT cells also con-

tribute to thermoregulation. The frequency of

gdT cells within adipose tissue increases after

cold exposure, and in the absence ofgdT cells

or IL-17A, mice exhibit decreased UCP1 ex-

pression and a greater loss of body temper-

ature ( 56 ), indicating thatgdT cells respond

to temperature fluctuations and maintain

homeostasis. More recently,gdT cells have

been shown to contribute to the adaptation

of gut epithelial cells to nutrient sensing ( 58 ).

Notch signaling was found to contribute to

the activation ofgdT cells in this context,

but it is important to highlight that in most

settings, the molecular mechanisms by which

unconventional T cells are activated and con-

tribute to host physiological responses remain

largely unknown.

Cutaneous MAIT cells are positioned below

the basement membrane, which serves as a

scaffold for the migration and attachment of

progenitor cells during wound healing ( 59 ).

MAIT cells are also found along the basement

membrane in the human colon ( 32 ), which

suggests that this may be a characteristic of

MAIT cells within epithelial tissues. In addi-

tion to their unique localization, MAIT cells

express a tissue repair transcriptional program,

which is enhanced by TCR-mediated stimula-

tion alone ( 4 , 31 , 32 ). However, when activated

in the presence of stimulatory cytokines, MAIT

cells acquire a distinct transcriptional profile

characterized by effector functions, with di-

minished expression of tissue repair genes

( 32 ). Similarly, in response to topically applied

Staphylococcus epidermidis, a skin commen-

sal that does not induce inflammation in this

manner ( 60 ), cutaneous MAIT cells up-regulate

the expression of genes associated with angio-

genesis and tissue repair, including angiogenin

and the growth factors IGF-1 and HGF ( 4 ). In

accordance with the notion that TCR activa-

tion promotes the tissue repair program of

MAIT cells, topical application of the stimula-

tory riboflavin derivative 5-OP-RU is sufficient

to increase re-epithelialization of cutaneous

excision wounds in wild-type mice. By con-

trast, MAIT cell–deficient animals exhibit less

wound healing, indicating that MAIT cells

contribute to tissue repair in vivo ( 4 ).

In iNKT cell–deficientTraj18–/–mice, cuta-

neous wound healing is delayed relative to

wild-type controls, in part due to decreased

collagen deposition and increased neutrophil

infiltration ( 61 , 62 ). However, theTraj18–/–mice

used in these studies were recently found to

lack MAIT cells in addition to iNKT cells be-

cause the null allele abrogates expression of

other Jagenes, including the invariantTraj33

used by the murine MAIT cell TCR ( 63 , 64 ),

making it impossible to distinguish the con-

tributions of these unconventional T cell

populations in this strain. Antibody blockade

of CD1d decreases iNKT cell frequency with-

in cutaneous wounds and promotes wound

Constantinides and Belkaid,Science 374 , eabf0095 (2021) 10 December 2021 4of6

Fig. 3. Unconventional T cells
within tissues.Shown are
the different populations of
effector lymphocytes present in
epithelial tissues, organized by
their effector molecules (columns)
and the extent of their innate
characteristics (rows). As a
consequence of their similar
transcriptional programs,
unconventional T cells express
overlapping cytokine receptors,
resulting in competition for
interleukins. Animal models defi-
cient 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.

NK

MAIT NKT

TC 1

ILC3

MAIT NKT

TH 17 TC 17

γδ T TC 17

ILC1

γδ T

TH 1 TH 2

ILC2

NKT

Innate

lymphoid cells

Unconventional

T cells

Conventional

T cells

Type 1 Type 2 Type 17

IL-12

I L-1 5

IL-18

I L-1

IL-18

IL-23

Innateness

Competition

IFN-γ, TNF-α IL-4, 5, 13 IL-17A, 17F, 22

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