Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 45, Pages 19402-19407Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1008247107
Keywords
IL-1; IL-17; IL-23; TGF-beta; CD4 T cells
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Funding
- Ludwig Institute for Cancer Research
- Cancer Research Institute
- Institut National de la Sante et de la Recherche Medicale (France)
- Institut National du Cancer (France)
- Conseil Regional des Pays de la Loire (France)
- European regional development fund
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ROR gamma 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-beta, 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 beta and is increased by IL-23 and TGF-beta. IL-1 beta-mediated differentiation correlated with IL-1RI expression in stimulated NTreg and was accompanied by induction of ROR gamma t along with down-regulation of FOXP3. IL-17-secreting cells in NTreg cultures cosecreted TNF-alpha and IL-2 and contained distinct subpopulations cosecreting or not cosecreting IFN-gamma 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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