IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells.
The development of T helper (T(H))17 and regulatory T (T(reg)) cells is reciprocally regulated by cytokines. Transforming growth factor (TGF)-beta alone induces FoxP3(+) T(reg) cells, but together with IL-6 or IL-21 induces T(H)17 cells. Here we demonstrate that IL-9 is a key molecule that affects differentiation of T(H)17 cells and T(reg) function. IL-9 predominantly produced by T(H)17 cells, synergizes with TGF-beta1 to differentiate naïve CD4(+) T cells into T(H)17 cells, while IL-9 secretion by T(H)17 cells is regulated by IL-23. Interestingly, IL-9 enhances the suppressive functions of FoxP3(+) CD4(+) T(reg) cells in vitro, and absence of IL-9 signaling weakens the suppressive activity of nT(regs) in vivo, leading to an increase in effector cells and worsening of experimental autoimmune encephalomyelitis. The mechanism of IL-9 effects on T(H)17 and T(regs) is through activation of STAT3 and STAT5 signaling. Our findings highlight a role of IL-9 as a regulator of pathogenic versus protective mechanisms of immune responses.
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Wassim
W
Elyaman
Elizabeth M
EM
Bradshaw
Catherine
C
Uyttenhove
Valérie
V
Dardalhon
Amit
A
Awasthi
Jaime
J
Imitola
Estelle
E
Bettelli
Mohamed
M
Oukka
Jacques
J
van Snick
Jean-Christophe
JC
Renauld
Vijay K
VK
Kuchroo
Samia J
SJ
Khoury
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D051858:Forkhead Transcription Factors / Q000502:physiology*; D020381:Interleukin-17 / Q000096:biosynthesis*; D053759:Interleukin-23 / Q000494:pharmacology; D016906:Interleukin-9 / Q000096:biosynthesis / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D050796:STAT3 Transcription Factor / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000502:physiology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; D016906:Interleukin-9; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; D053773:Transforming Growth Factor beta1