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Human RORγt⁺ T H 17 cells preferentially differentiate from naive FOXP3⁺Treg in the presence of lineage-specific polarizing factors
Danila Valmori, Caroline Raffin, Isabelle Raimbaud, Maha Ayyoub and Lloyd J. Old
Proceedings of the National Academy of Sciences of the United States of America
Vol. 107, No. 45 (November 9, 2010), pp. 19402-19407
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/25748686
Page Count: 6
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RORγt⁺ T H 17 cells are a proinflammatory CD4⁺ T-cell population associated with autoimmune tissue injury. In mice, priming of T H 17 requires TGF-β, which alone directs the priming of FOXP3⁺ regulatory T cells (Treg), in association with inflammatory cytokines. Priming of human T H 17 cells from conventional naive CD4⁺ T cells under similar conditions, however, has proved difficult to achieve. Here, we report that differentiation of human T H 17 cells preferentially occurs from FOXP3⁺ naive Treg (NTreg) in the presence of IL-2 and IL-1β and is increased by IL-23 and TGF-β. IL-1β–mediated differentiation correlated with IL-1RI expression in stimulated NTreg and was accompanied by induction of RORγt along with down-regulation of FOXP3. IL-17–secreting cells in NTreg cultures cosecreted TNF-α and IL-2 and contained distinct subpopulations cosecreting or not cosecreting IFN-γ and other T H 17-associated cytokines. Polarized NTreg contained significant subpopulations of CCR6-expressing cells that were highly enriched in IL-17–secreting cells. Finally, analysis of CCR6 expression with respect to that of IL-1RI identified distinct IL-17–secreting subpopulations that had maintained or lost their suppressive functions. Together our results support the concept that priming of human T H 17 from naive CD4⁺ T cells preferentially takes place from FOXP3⁺ Treg precursors in the presence of lineage-specific polarizing factors.
Proceedings of the National Academy of Sciences of the United States of America © 2010 National Academy of Sciences