Molecular antagonism and plasticity of regulatory and inflammatory T cell programs.
Regulatory T (Treg) and T helper 17 (Th17) cells were recently proposed to be reciprocally regulated during differentiation. To understand the underlying mechanisms, we utilized a Th17 reporter mouse with a red fluorescent protein (RFP) sequence inserted into the interleukin-17F (IL-17F) gene. Using IL-17F-RFP together with a Foxp3 reporter, we found that the development of Th17 and Foxp3(+) Treg cells was associated in immune responses. Although TGF-beta receptor I signaling was required for both Foxp3 and IL-17 induction, SMAD4 was only involved in Foxp3 upregulation. Foxp3 inhibited Th17 differentiation by antagonizing the function of the transcription factors RORgammat and ROR*. In contrast, IL-6 overcame this suppressive effect of Foxp3 and, together with IL-1, induced genetic reprogramming in Foxp3(+) Treg cells. STAT3 regulated Foxp3 downregulation, whereas STAT3, RORgamma, and ROR* were required for IL-17 expression in Treg cells. Our data demonstrate molecular antagonism and plasticity of Treg and Th17 cell programs.
Yang
Xuexian O
XO
Department of Immunology, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Nurieva
Roza
R
Martinez
Gustavo J
GJ
Kang
Hong Soon
HS
Chung
Yeonseok
Y
Pappu
Bhanu P
BP
Shah
Bhavin
B
Chang
Seon Hee
SH
Schluns
Kimberly S
KS
Watowich
Stephanie S
SS
Feng
Xin-Hua
XH
Jetten
Anton M
AM
Dong
Chen
C
D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D014161:Transduction, Genetic; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism
D020381:Interleukin-17; D053773:Transforming Growth Factor beta1