IL-9 induces differentiation of TH17 cells and enhances function of FoxP3⁺ natural regulatory T cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 31; pp. 12885 - 12890
• Main Authors: Elyaman, Wassim, Bradshaw, Elizabeth M, Uyttenhove, Catherine, Dardalhon, Valérie, Awasthi, Amit, Imitola, Jaime, Bettelli, Estelle, Oukka, Mohamed, van Snick, Jacques, Renauld, Jean-Christophe, Kuchroo, Vijay K, Khoury, Samia J
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 04.08.2009; National Acad Sciences
• Subjects: Amino Acid Sequence; Animals; Biological Sciences; Cell Differentiation - drug effects; Female; Forkhead Transcription Factors - physiology; Interleukin-17 - biosynthesis; Interleukin-23 - pharmacology; Interleukin-9 - biosynthesis; Interleukin-9 - pharmacology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Molecular Sequence Data; STAT3 Transcription Factor - physiology; STAT5 Transcription Factor - physiology; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - physiology; Transforming Growth Factor beta1 - pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0812530106

The development of T helper (TH)17 and regulatory T (Treg) cells is reciprocally regulated by cytokines. Transforming growth factor (TGF)-β alone induces FoxP3⁺ Treg cells, but together with IL-6 or IL-21 induces TH17 cells. Here we demonstrate that IL-9 is a key molecule that affects differentiation of TH17 cells and Treg function. IL-9 predominantly produced by TH17 cells, synergizes with TGF-β1 to differentiate naïve CD4⁺ T cells into TH17 cells, while IL-9 secretion by TH17 cells is regulated by IL-23. Interestingly, IL-9 enhances the suppressive functions of FoxP3⁺ CD4⁺ Treg cells in vitro, and absence of IL-9 signaling weakens the suppressive activity of nTregs in vivo, leading to an increase in effector cells and worsening of experimental autoimmune encephalomyelitis. The mechanism of IL-9 effects on TH17 and Tregs 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.