Science - USA (2022-04-15)

INSIGHTS | PERSPECTIVES

244 15 APRIL 2022 • VOL 376 ISSUE 6590

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lupus-like autoimmune disease with mas-
sive expansion of CD4+ T follicular helper
(T FH) cells and germinal centers despite
normal virus clearance. This is consis-
tent with previous findings that mouse
Ly49F+CD8+ T cells can kill activated TFH
cells and thereby prevent excessive activa-
tion of germinal centers and production of
pathogenic antibodies ( 4 ). It also suggests,
as proposed by Li et al., that CD8+ regula-
tory T cells are not involved in suppress-
ing pathogenic immune responses in viral
infections (e.g., COVID-19 and influenza)
but rather limit the damage induced by
autoreactive T cells that are cross-reactive
to foreign antigens ( 3 , 7 ). Overall, Li et al.
show that a subset of CD8+ T cells express-
ing Ly49F in mice and KIR in humans
can exert feedback control on autoimmune
and/or pathogenic CD4+ T cells (see the
figure). However, many gaps in our under-
standing remain.
It is unclear what is the nature of the
signal or signals that induce the activation
of regulatory KIR+CD8+ T cells and enable
the selective killling of antigen-specific
CD4+ T cells. In mice, the regulatory func-
tion of Ly49F+CD8+ T cells is triggered by
engagement of their TCR by endogenous
peptides presented by either classical or
nonclassical class I major histocompatibil-
ity complexes (MHCs) ( 2 , 4 ). This may also
be true for human KIR+CD8+ T cells and
implies that the endogenous antigens rec-
ognized by KIR+CD8+ T cells are selectively
expressed by chronically activated CD4+ T
cells. Indeed, recognition of self-antigens
by CD8+ T cells is a major mechanism driv-
ing tissue destruction in autoimmune dis-
eases. In a mouse model of type I diabetes,
disease-causing CD8+ T cells that killed
pancreatic cells were recently identified.
Comparing transcriptomes and TCR rep-
ertoires of autoimmune CD8+ T cells and

KIR+CD8+ T cells may help to understand

whether their opposite functions derive from

distinct differentiation programs or from

their recognition of endogenous peptides ex-

pressed by different cellular targets ( 8 ).

Evidence that the suppressor function

of Ly49F+CD8+ T cells can be activated by

peptides expressed by pathogenic CD4+ T

cells was obtained in a mouse model of

multiple sclerosis. In this model, driven by

pathogenic CD4+ T cells directed against a

myelin-specific autoantigen, MHC class I–

restricted peptides that selectively bound

the TCRs of the protective Ly49F+CD8+ T

cells were identified ( 2 ). Moreover, immuni-

zation of mice with these peptides elicited

Ly49F+CD8+ T cells that protected against

disease and killed the pathogenic myelin-

specific CD4+ T cells. This effect was disease

specific because no protection was observed

against autoimmune uveitis induced by an

eye-specific autoantigen ( 2 ). It will be in-

teresting to extend these findings to hu-

mans and to define whether protection by

KIR+CD8+ T cells is disease specific.

The mechanisms that drive the differ-

entiation, expansion, and activation of

KIR+CD8+ T cells are also important un-

knowns. A hallmark of these cells is their

expression of KIR. This seems to be the

consequence of their chronic activation,

although the exact mechanism remains

to be elucidated. Studies in mice suggest

that KIR could promote their survival ( 9 )

but also attenuate their regulatory func-

tion ( 10 ). Another important feature of

KIR+CD8+ T cells is their expression of

Helios. This transcription factor maintains

the regulatory function of Ly49F+CD8+ T

cells, at least partly through its role in pro-

moting transcription downstream of signal

transducer and activator of transcription

5 (STAT5) ( 6 ). This is consistent with the

established role of interleukin-15 (IL-15),

a cytokine that signals mainly through

STAT5, in the survival of Ly49F+CD8+ T

cells in vivo ( 4 ). However, this further

blurs the distinction from other cytotoxic

CD8+ T cells that are also dependent on

IL-15 for survival ( 11 ). This is notably the

case in CeD, in which CD8+ intraepithelial

lymphocytes activated through coopera-

tive interactions between CD4+ T cells and

IL-15 are thought to play a major role in

tissue destruction ( 12 , 13 ). There is cur-

rently much interest in the therapeutic

modulation of IL-15 to enhance antitumor

responses or, conversely, to inhibit autoim-

mune tissue destruction. If both effector

and regulatory CD8+ T cells rely on IL-15

for survival and activation, this strategy

should be considered carefully.

Overall, Li et al. unveil an intriguing

population of human regulatory CD8+ T

cells that can suppress inflammatory re-

sponses through killing activated patho-

genic T cells. Targeting KIR+CD8+ T cells

might emerge as a new strategy to sup-

press undesirable self-reactivity in autoim-

mune or infectious diseases. j

REFERENCES AND NOTES

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3. J. Li et al., Science 376 , eabi9591 (2022).


4. H. Nakagawa, L. Wang, H. Cantor, H.-J. Kim, Adv.
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5. B. Jabri, L. M. Sollid, J. Immunol. 198 , 3005 (2017).


6. H.-J. Kim et al., Science 350 , 334 (2015).


7. L. F. Su, B. A. Kidd, A. Han, J. J. Kotzin, M. M. Davis,
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8. S. V. Gearty et al., Nature 602 , 156 (2022).


9. S. Ugolini et al., Nat. Immunol. 2 , 430 (2001).


10. L. Lu, H.-J. Kim, M. B. F. Werneck, H. Cantor, Proc. Natl.
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11. J. C. Nolz, M. J. Richer, Mol. Immunol. 117 , 180 (2020).


12. V. Abadie et al., Nature 578 , 600 (2020).


13. N. Korneychuk et al., Gastroenterology 146 , 1017
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10.1126/science.abp8243

Control of antibody production

Pathogenic

antibodies

B cell Activated

CD4+ TFH cell

Control of T cell–immune responses Tissue damage

Virus

elimination

Germinal center

T cell help

CD4+ T cell

Autoreactive T cells

CD8+KIR– T cell

Chronic activation

CD4+FOXP3– Treg cell

Killing of autoreactive

or pathogenic CD4+ T cells

KIR

CD8+KIR+ T cell

CD4+ T cell

Regulatory CD8+ T cells control pathogenic immune responses
During immune responses against pathogens and viruses, activated CD4+ T cells provide help to B cells that produce neutralizing antibodies and to CD8+ T cells that
kill infected host cells. Chronic activation of immune responses can cause tissue damage. Human CD8+ T cells expressing the inhibitory killer cell immunoglobulin-like
receptors (KIRs) KIR3DL1 and/or KIR2DL3 expand during chronic inflammation and kill activated pathogenic CD4+ T cells and T follicular helper (TFH) cells, complementing
the regulatory functions of forkhead box P3 (FOXP3)+ CD4+ Treg cells.