Science - USA (2019-01-04)

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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