Human RORγt+ TH17 cells preferentially differentiate from naive FOXP3+Treg in the presence of lineage-specific polarizing factors.
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.
Institut National de la Santé et de la Recherche Médicale, Unité 892, Centre de Lutte Contre le Cancer René Gauducheau, 44800 Saint Herblain, France. Danila.Valmori@univ-nantes.fr
Danila
D
Valmori
Caroline
C
Raffin
Isabelle
I
Raimbaud
Maha
M
Ayyoub
D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage; D051858:Forkhead Transcription Factors; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D007378:Interleukins / Q000494:pharmacology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D058504:Th17 Cells / Q000166:cytology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D020381:Interleukin-17; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D016212:Transforming Growth Factor beta