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Human ROR?t+ TH17 cells preferentially differentiate from naive FOXP3+Treg in the presence of lineage-specific polarizing factors.


ABSTRACT: ROR?t(+) 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-?, 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-1? and is increased by IL-23 and TGF-?. IL-1?-mediated differentiation correlated with IL-1RI expression in stimulated NTreg and was accompanied by induction of ROR?t along with down-regulation of FOXP3. IL-17-secreting cells in NTreg cultures cosecreted TNF-? and IL-2 and contained distinct subpopulations cosecreting or not cosecreting IFN-? 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.

SUBMITTER: Valmori D 

PROVIDER: S-EPMC2984184 | BioStudies | 2010-01-01

REPOSITORIES: biostudies

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