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Journal Article

TRAF6 inhibits Th17 differentiation and TGF-beta-mediated suppression of IL-2

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Pearce,  Erika L.
Department Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

External Resource

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2890173/
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Cejes et al..pdf
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Citation

Cejas, P. J., Walsh, M. C., Pearce, E. L., Han, D., Harms, G. M., Artis, D., et al. (2012). TRAF6 inhibits Th17 differentiation and TGF-beta-mediated suppression of IL-2. Blood, 115, 4750-4757. doi:10.1182/blood-2009-09-242768.


Cite as: https://hdl.handle.net/21.11116/0000-0006-612A-E
Abstract
Transforming growth factor-β (TGF-β) 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-β–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-β–induced Smad2/3 activation and proliferation arrest. Consistent with this, in TRAF6-deficient T cells, TGF-β 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-β signaling and Th17 differentiation. Importantly, the data also suggest that a main function of TGF-β in early Th17 differentiation may be the inhibition of autocrine and paracrine IL-2–mediated suppression of Th17 cell generation.