TRAF6 inhibits Th17 differentiation and TGF-beta-mediated suppression of IL-2.
Transforming growth factor-beta (TGF-beta) has an essential role in the generation of inducible regulatory T (iTreg) and T helper 17 (Th17) cells. However, little is known about the TGF-beta-triggered pathways that drive the early differentiation of these cell populations. Here, we report that CD4(+) T cells lacking the molecular adaptor tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) exhibit a specific increase in Th17 differentiation in vivo and in vitro. We show that TRAF6 deficiency renders T cells more sensitive to TGF-beta-induced Smad2/3 activation and proliferation arrest. Consistent with this, in TRAF6-deficient T cells, TGF-beta more effectively down-regulates interleukin-2 (IL-2), a known inhibitor of Th17 differentiation. Remarkably, TRAF6-deficient cells generate normal numbers of Foxp3-expressing cells in iTreg differentiation conditions where exogenous IL-2 is supplied. These findings show an unexpected role for the adaptor molecule TRAF6 in Smad-mediated TGF-beta signaling and Th17 differentiation. Importantly, the data also suggest that a main function of TGF-beta in early Th17 differentiation may be the inhibition of autocrine and paracrine IL-2-mediated suppression of Th17 cell generation.
Cejas
Pedro J
PJ
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Walsh
Matthew C
MC
Pearce
Erika L
EL
Han
Daehee
D
Harms
Gretchen M
GM
Artis
David
D
Turka
Laurence A
LA
Choi
Yongwon
Y
D000818:Animals; D019898:Autocrine Communication / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D019899:Paracrine Communication / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051899:Smad2 Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D048029:TNF Receptor-Associated Factor 6; D016212:Transforming Growth Factor beta