RESEARCH ARTICLE SUMMARY
◥IMMUNOLOGY
Commensal-specific T cell
plasticity promotes rapid tissue
adaptation to injury
Oliver J. Harrison, Jonathan L. Linehan, Han-Yu Shih, Nicolas Bouladoux,
Seong-Ji Han, Margery Smelkinson, Shurjo K. Sen, Allyson L. Byrd, Michel Enamorado,
Chen Yao, Samira Tamoutounour, Francois Van Laethem, Charlotte Hurabielle,
Nicholas Collins, Andrea Paun, Rosalba Salcedo, John J. O’Shea, Yasmine Belkaid*
INTRODUCTION:Barrier tissues are con-
stitutive targets of environmental stressors
and are home to a highly diverse microbiota.
When the immune system encounters these
noninvasive microbes, one possible result is
the induction of cognate T cell responses that
control various aspects of tissue function, in-
cluding antimicrobial defense and tissue re-
pair. Given the extraordinary number of antigens
expressed by the microbiota, a substantial frac-
tion of barrier tissue–resident T cells are ex-
pected to be commensal-specific, accumulating
over time in response to successive exposure to
new commensals. Because barrier tissues are
defined by the constitutive coexistence of com-
mensals and commensal-reactive lymphocytes,
any understanding of tissue homeostasis, re-
sponse to injury, and tissue-specific pathologies
must occur in the context of this fundamental
dialog.
RATIONALE:The skin serves as a primary
interface with the environment and is conse-
quently a constitutive target of environmental
stressors mediated by physical damage or in-
vasive pathogens. Tissue protection from these
challenges relies on rapid and coordinated local
responses tailored to both the microenviron-
ment and the nature of the instigating injury.
Our study explored whether commensal-specific
T cells can act as tissue sentinels, allowing rapid
adaptation to defined injuries, and how dys-
regulationoftheseresponsesmayhavepath-
ogenic consequences.RESULTS:Homeostatic encounters with com-
mensal microbes promoted the induction of
commensal-specific interleukin-17A (IL-17A)–
producing T cells [CD4+(TH17) and CD8+(TC17)]
that persisted as tissue-resident memory cells.
Surprisingly, commensal-specific T cells were
characterized by coexpression of classically an-
tagonistic transcription factors (RORgt and
GATA-3) that control the respective expression
of type 17 and type 2 programs. Consequently,
commensal-specific T cells displayed a hybrid
chromatin landscape that underlies the co-
expression of a broad type 2 transcriptome,
including the type 2 effector cytokines IL-5
and IL-13. Notably, during homeostasis, RORgt+
T cells expressed type 2 cytokine mRNA without
subsequent protein translation. By contrast, inthe context of tissue challenges such as chitin
injection or insect bites, commensal-specific
RORgt+T cells were able to produce type 2
cytokines (IL-5 and IL-13). The spontaneous
release of type 2 cytokines by these cells was
also observed in the context of local defects
in immune regulation associated with impaired
regulatory T cell function. Alarmins associated
with tissue damage and inflammation, such
as IL-1, IL-18, IL-25, and IL-33, were able to
superimpose a type 2 effector program on
both TC17 and TH17 cells
in the context of T cell re-
ceptor engagement. Using
an IL-17A fate-mapping
strategy, we found that
IL-17A–committed RORgt+
TcellsandtheirIL-17A−
RORgt+counterparts both produced type 2
cytokines in response to tissue alarmins. Such
cellular plasticity allows commensal-specific
type 17 cells to promote IL-17A–mediated
antimicrobial defense under homeostatic con-
ditions, as well as tissue repair in an IL-13–
dependent manner in the context of tissue
injury.CONCLUSION:Our work describes a tissue
checkpoint that relies on the remarkable
plasticity and adaptability of tissue-resident
commensal-specific T cells. We propose that
this feature may also have important implica-
tions in the etiology of tissue-specific inflam-
matory disorders. The extraordinary number
of both commensal-derived antigens and T cells
at barrier sites suggests that the ability of
commensal-specific T cells to functionally
adapt to injury may play a fundamental role in
controlling tissue physiology.▪RESEARCH
Harrisonet al.,Science 363 , 43 (2019) 4 January 2019 1of1
The list of author affiliations is available in the full article online.
*Corresponding author. Email: [email protected]
Cite this article as O. J. Harrisonet al.,Science 363 , eaat6280
(2019). DOI: 10.1126/science.aat6280Tissue injury Impaired regulationAntimicrobial
defenseMicrobiotaHomeostasisIl5,
Il13 mRNAPoised type 2
immunityAlarmin-licensed
T cell plasticityIL-13Wound
repairCommensal-specific
CD4+ and CD8+ T cellsTissue
InflammationFoxp3+ TregIL-5
IL-13IL-17A
IL-1
IL-18
IL-25
IL-33AlarminsPoised type 2 immunity of commensal-specific T cells promotes rapid adaptation to tissue injury.Commensal-specific T cells produce
IL-17A under homeostatic conditions for antimicrobial defense while harboring a poised type 2 transcriptome. Tissue injury licenses type 2
immune potential of commensal-specific type 17 T cells, thereby promoting tissue repair. Impaired immune regulation unleashes type 2
cytokine production from commensal-specific CD8+TC17 cells.
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at http://dx.doi.
org/10.1126/
science.aat6280
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