Science - USA (2020-01-17)

INSIGHTS | PERSPECTIVES

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This continuous TCR “tickling” is thought to
support the maintenance of peripheral naïve
T cells ( 2 ), which undergo activation, clonal
expansion, and differentiation into effector T
cells when they encounter their cognate an-
tigen during inflammation.
More than 100 years ago, the pioneering
physician and scientist Paul Ehrlich noted
that the immune system of higher organ-
isms can turn against the organism, lead-
ing to the development of autoimmunity.
Decades later, it was proposed that there
are two signals for T cell activation—one
transmitted through the TCR and a second
transmitted through a costimulatory recep-
tor ( 3 , 4 ). Discovery of CD28 as the princi-
pal costimulatory receptor, with CD80 and
CD86 as its ligands, provided support for
this model. The subsequent discovery that
expression of these costimulatory molecules
was directly linked to sensing of microbial
ligands by evolutionary conserved pattern
recognition receptors (for example, Toll-like
receptors) provided the basis for a two-sig-
nal model of naïve T cell activation that in-
tegrates innate and adaptive receptor cues
( 5 ). This suggests that self-reactivity is lim-
ited in a “passive” manner through lack of
a permissive second signal (CD80 or CD86).
Another layer of regulation has been iden-
tified through the discovery of inhibitory
receptors, CTLA-4 (cytotoxic T-lymphocyte–
associated antigen 4) and PD-1 (programmed
cell death protein 1), that are induced upon
activation of T cells to dampen their re-
sponses ( 6 ). These mechanisms represent an
“active” mode of reinforcement of self-toler-
ance through limiting TCR and CD28 signal-
ing. The importance of this active pathway
in limiting self-reactivity is demonstrated by
genetic studies in mice as well as therapeutic
targeting of these receptors in cancer, both
of which can lead to the development of au-
toimmunity ( 7 ).
ElTanbouly et al. reveal a role for VISTA
(V-type immunoglobulin domain-contain-
ing suppressor of T-cell activation), an in-
hibitory receptor that is homologous to the
PD-1 ligand, PDL1 ( 8 ), in preventing activa-
tion of naïve T cells in the absence of in-
flammation. Mice deficient in VISTA have
increased frequencies of effector T cells
and, in some instances, develop autoimmu-
nity ( 9 , 10 ). On myeloid cells, VISTA acts as
an inhibitory ligand. However, T cells also
have low expression of VISTA, where it may
act as an inhibitory receptor ( 11 ). ElTan-
bouly et al. show that constitutive expres-
sion of VISTA by T cells in homeostasis acts
as a brake to restrain inappropriate naïve
T cell activation. This indicates that naïve
T cell quiescence is actively maintained to
prevent inappropriate activation and ensu-
ing autoimmunity (see the figure).

Despite the checkpoints in place to pre-

vent autoimmunity, a small proportion

of naïve T cells spontaneously convert to

memory-like CD4+ T cells, possibly in re-

sponse to self-antigen recognition ( 12 ).

ElTanbouly et al. provide evidence that

VISTA may serve as a critical T cell–in-

trinsic mechanism for preventing this “ho-

meostatic” conversion of naïve to effector

T cells. Using single-cell RNA sequencing,

they identified a dominant cluster of naïve

CD4+ T cells in healthy mice distinguished

by high expression of transcription factors

known to regulate T cell quiescence ( 13 ).

Although thymic naïve CD4+ T cells also

express VISTA, its loss in mice did not af-

fect their phenotype until after they left

the thymus. This suggests that VISTA acts

to prevent T cell activation in response to

signals received in the periphery.

Do these shifts in naïve T cell phenotypes

require TCR signaling? Providing further

support for a model whereby TCR engage-

ment, potentially by self or innocuous non-

self antigens, drives conversion of naïve T

cells to memory-like CD4+ cells in steady

state, ElTanbouly et al. demonstrate that

VISTA specifically suppresses clonal expan-

sion of naïve T cells after engagement of the

TCR in the absence of costimulation.

These findings point to active regula-

tion of naïve T cell quiescence as a critical

mechanism for the prevention of autoim-

munity. The interacting partner for VISTA

was recently identified as P-selectin gly-

coprotein ligand 1 (PSGL-1) ( 14 ), which is

not only expressed on the surface of both

myeloid and activated T cells but also on

resting T cells, albeit at a lower amount.

Further elaboration of this signaling path-

way is needed to understand how VISTA

regulates T cell quiescence. Understanding

the signals that act upstream of VISTA will

be important for harnessing this immune-

modulatory pathway: either enhancing

naïve T cell responses in settings of vaccina-

tion or suppressing T cell activation during

autoimmunity. Although clonally expanded

T cells have been identified in human auto-

immune disease, the majority of memory T

cells at sites of inflammation are not clon-

ally expanded, suggesting a substantial

contribution of “bystander” memory cells

of unrelated antigenic specificity to chronic

inflammation ( 15 ). The study of ElTanbouly

et al. suggests that therapeutic targeting of

VISTA may limit the generation of these by-

stander cells and could be a potential strat-

egy for suppressing inflammation. j

REFERENCES AND NOTES

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3. P. Bretscher, M. Cohn, Science 169 , 1042 (1970).


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5. R. Medzhitov, P. Preston-Hurlburt, C. A. Janeway Jr.,
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6. J. Attanasio, E. J. Wherry, Immunity 44 , 1052 (2016).


7. Q. Zhang, D. A. A. Vignali, Immunity 44 , 1034 (2016).


8. L. Wang et al., J. Exp. Med. 208 , 577 (2011).


9. L. Wang et al., Proc. Natl. Acad. Sci. U.S.A. 111 , 14846
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10. X. Han et al., Sci. Transl. Med. 11 , eaax1159 (2019).


11. D. B. Flies et al., J. Clin. Invest. 124 , 1966 (2014).


12. T. Kawabe et al., Sci. Immunol. 2 , eaam9304 (2017).


13. X. Feng et al., Nat. Immunol. 12 , 544 (2011).


14. R. J. Johnston et al., Nature 574 , 565 (2019).


15. N. Saligrama et al., Nature 572 , 481 (2019).

ACKNOWLEDGMENTS

C.B. is supported by a Wellcome Trust Fellowship; A.Y.R. is sup-

ported by the Howard Hughes Medical Institute, the Ludwig

Center at Memorial Sloan Kettering, and the Parker Institute

for Cancer Immunotherapy (PICI). This work was supported

by NIH–National Cancer Institute (NCI) Cancer Center

Support Grant (CCSG) P30CA008748.

10.1126/science.aaz7741

NaïveCD4+

T cell

Self-antigen

Antigen-presenting cell

VISTA

Passive tolerance

Active

tolerance

Cell death

Memory

T cell

P-selectin

glycoprotein

ligand 1

CD28 TCRCD4

MHC II

MHC II, major histocompatibility complex type II; TCR, T cell receptor;

VISTA, V-type immunoglobulin domain-containing suppressor

of T-cell activation.

Naïve T cell tolerance

TCRs recognize self-antigens bound to MHC II

molecules. In passive tolerance, naïve T cells that

recognize MHC II–self-antigen in the absence of

costimulatory CD80 or CD86 become hyporeactive.

In active tolerance, VISTA promotes naïve T cell death

and prevents conversion to the memory phenotype

after self-antigen recognition.

248 17 JANUARY 2020 • VOL 367 ISSUE 6475

Published by AAAS