STAT3 regulates cytokine-mediated generation of inflammatory helper T cells.
Interleukin-17 (IL-17)-producing helper T (TH) cells, named as TH(IL-17), TH17, or inflammatory TH (THi), have been recently identified as a novel effector lineage. However, how cytokine signals mediate THi differentiation is unclear. We found that IL-6 functioned to up-regulate IL-23R and that IL-23 synergized with IL-6 in promoting THi generation. STAT3, activated by both IL-6 and IL-23, plays a critical role in THi development. A hyperactive form of STAT3 promoted THi development, whereas this differentiation process was greatly impaired in STAT3-deficient T cells. Moreover, STAT3 regulated the expression of retinoic acid receptor-related orphan receptor gamma-T (RORgamma t), a THi-specific transcriptional regulator; STAT3 deficiency impaired RORgamma t expression and led to elevated expression of T-box expressed in T cells (T-bet) and Forkhead box P3 (Foxp3). Our data thus demonstrate a pathway whereby cytokines regulate THi differentiation through a selective STAT transcription factor that functions to regulate lineage-specific gene expression.
Yang
Xuexian O
XO
Department of Immunology, M.D. Anderson Cancer Center, Houston, Texas 77030.
Panopoulos
Athanasia D
AD
Department of Immunology, M.D. Anderson Cancer Center, Houston, Texas 77030.
Nurieva
Roza
R
Department of Immunology, M.D. Anderson Cancer Center, Houston, Texas 77030.
Chang
Seon Hee
SH
Department of Immunology, M.D. Anderson Cancer Center, Houston, Texas 77030.
Wang
Demin
D
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin 53226.
Watowich
Stephanie S
SS
Department of Immunology, M.D. Anderson Cancer Center, Houston, Texas 77030.
Dong
Chen
C
Department of Immunology, M.D. Anderson Cancer Center, Houston, Texas 77030. Electronic address: cdong@mdanderson.org.
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050796:STAT3 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism / Q000473:pathology*
D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D007371:Interferon-gamma