to promote these responses (fig. S6C). Thus, the
poised type 2 immune potential of commensal-
specific TC17 cells allows for local adaptation to
injury, thereby promoting tissue repair.
Conclusion
Barrier tissues are constitutively exposed to en-
vironmental stressors and are primary targets of
chronic inflammatory disorders. The mainte-
nance of tissue integrity and function represent
a complex challenge that requires both resilience
and adaptation. Under steady-state conditions,
tissue resilience is, in part, mediated by innate
and adaptive immunity to the microbiota, which
reinforces barrier function and immunity ( 5 ).
Our results show that adaptation of tissue to
injuries can also be mediated by immunity to
the microbiota, a fundamental but poorly under-
stood class of immunity. Notably, we found that
homeostatic immunity to bacteria or fungal com-
mensals is characterized by the coexpression of
paradoxical programs, allowing commensal-
specific T cells, when entering and persisting
within tissues, to adopt a type 17 program com-
patiblewithtissuehomeostasisandimmunity
while maintaining a type 2–poised state. As such,
in the context of injury and consequent exposure
to inflammatory mediators and cognate antigens,
commensal-specific T cells rapidly release type 2
cytokines, allowing these cells to exert pleiotropic
and contextual functionsincluding tissue repair.
Thus,wedescribeatissuecheckpointthatrelies
ontheremarkableplasticityandadaptabilityof
tissue-resident commensal-specific T cells. We pro-
pose that this feature may also have important
implications in the etiology of tissue-specific
inflammatory disorders. Given the extraordinary
number of both commensal-derived antigens and
T cells at barrier sites, such a feature may represent
a fundamental component of host immunity.
Materials and methods
Mice
Wild-type (WT) C57BL/6 Specific Pathogen
Free(SPF)micewerepurchasedfromTaconic
Harrisonet al.,Science 363 , eaat6280 (2019) 4 January 2019 7of11
AB
MediaIL-1
α
IL-1
β
IL-18IL-25IL-33TSLP
0
0.5
1.0
1.5
2.0
IL-17A (ng/ml)
*
*
Tc17
C D
0
50
100
150
IFN-
γ (ng/ml)
MediaIL-1
α
IL-1
β
IL-18IL-25IL-33TSLP
Tc1
**
**
MediaIL-1
α
IL-1
β
IL-18IL-25IL-33TSLP
0
50
100
150
200
IL-5 (pg/ml)
Tc17
**
**
**
MediaIL-1
α
IL-1
β
IL-18IL-25IL-33TSLP
0
100
200
300
400
500
IL-13 (pg/ml)
Tc17
**
*
*
*
EF
i.d. PBS i.d. IL-18
IL-17A
IL-5
25±4 0.2±0.1
0.6±0.3
16±5 4±2
15±3
Tc17
G
22±4 1±0.3
2±1
3±1 0
3±1
10±3 3±2
17±5
2±1 0.3±0.1
18±4
IL-17A
CD4+ CCR6+
i.d. PBS
IL-5
CD4+ CCR6+
i.d. IL-18
CD4+ CCR6-
i.d. PBS
CD4+ CCR6-
i.d. IL-18
i.d. PBS
i.d. IL-18
**
0
5
10
15
20
IL-5
+ (%)
Tc1 Tc17
0
5
10
IL-13
+ (%)
**
Tc1 Tc17
0
5
10
15
20
25
IFN-
+γ
(%)
Tc1 Tc17
IL-17A
+ (%)
0
Tc1 Tc17
10
20
30 *
H
I
Chitin
*
0
5
10
15
20
PBS IL-18
*
IL-5
+ Th17 (%)
Chitin
*
0
2
4
6
8
IL-13
+ Th17 (%)
PBS IL-18
*
0
5
10
15
20
PBSIL-18
*
Chitin
*
IL-5
+ Tc17 (%)
0
2
4
6
8
IL-13
+ Tc17 (%)
PBS Chitin
*
IL-18
*
Il18r1fl/fl Cd4CreIl18r1fl/fl
Il18r1fl/fl Cd4CreIl18r1fl/fl
Fig. 5. Tissue alarmins license type 2 cytokine production from commensal-specific
T cells.(AtoD)TC17 (CD8+CCR6+) and TC1 (CD8+CCR6−) cells were isolated from
the skin ofS. epidermidis–colonized wild-type mice and cultured in vitro with agonistic
anti-CD3emAb and the indicated cytokines. Cell culture supernatants were assayed
for cytokine production after 24 hours of culture. (E) Representative contour plots
of IL-5 and IL-17A production potential byS. epidermidis–induced TC17 cells after i.d.
injection with PBS or IL-18. (F) Representative contour plots of IL-5 and IL-17A production
potential by skin CD4+Foxp3−T cells fromS. epidermidis–colonized wild-type mice after
i.d. injection with PBS or IL-18. (G) Frequencies of TC17 and TC1 cells with indicated
cytokine production potential from the skin ofS. epidermidis–colonized wild-type mice
after i.d. injection of PBS or IL-18. (HandI) Frequencies of TC17 (H) and TH17 (I) cells with
indicated cytokine production potential from the skin ofS. epidermidis–colonized
Cd4CreIl18r1fl/fland control mice after i.d. injection with PBS, IL-18, or chitin. Numbers in
representative plots indicate means ± SD. Bar graphs show means ± SD. Data represent at least two experiments with three to six mice per group.
*P< 0.05, **P< 0.01 as calculated using one-way [(A) to (D), (G)] or two-way [(H), (I)] ANOVA with Holm-Šidák multiple-comparison test.
RESEARCH | RESEARCH ARTICLE
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