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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
Stable URL: http://www.jstor.org/stable/25748686
Page Count: 6
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Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Human RORγt⁺ T
          H
          17 cells preferentially differentiate from naive FOXP3⁺Treg in the presence of lineage-specific polarizing factors
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Abstract

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.

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