Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Autocrine Communication / genetics
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Autocrine Communication / immunology
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Cell Proliferation
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / immunology
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Forkhead Transcription Factors / metabolism
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Immune Tolerance / genetics
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Immune Tolerance / immunology
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Interleukin-2 / genetics
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Interleukin-2 / immunology*
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Interleukin-2 / metabolism
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Mice
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Mice, Mutant Strains
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Paracrine Communication / genetics
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Paracrine Communication / immunology
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Smad2 Protein / genetics
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Smad2 Protein / immunology
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Smad2 Protein / metabolism
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Smad3 Protein / genetics
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Smad3 Protein / immunology
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Smad3 Protein / metabolism
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T-Lymphocytes, Helper-Inducer
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TNF Receptor-Associated Factor 6 / genetics
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TNF Receptor-Associated Factor 6 / immunology*
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TNF Receptor-Associated Factor 6 / metabolism
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / immunology*
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Transforming Growth Factor beta / metabolism
Substances
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Interleukin-2
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Smad2 Protein
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Smad2 protein, mouse
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Smad3 Protein
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Smad3 protein, mouse
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TNF Receptor-Associated Factor 6
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Transforming Growth Factor beta