Article abstract
Nature Immunology 9, 641 - 649 (2008)
Published online: 4 May 2008 | doi:10.1038/ni.1610
The differentiation of human TH-17 cells requires transforming growth factor-
and induction of the nuclear receptor ROR
t
Nicolas Manel1, Derya Unutmaz2 & Dan R Littman1,2,3,4
Abstract
TH-17 cells are interleukin 17 (IL-17)–secreting CD4+ T helper cells involved in autoimmune disease and mucosal immunity. In naive CD4+ T cells from mice, IL-17 is expressed in response to a combination of IL-6 or IL-21 and transforming growth factor-
(TGF-) and requires induction of the nuclear receptor ROR
t. It has been suggested that the differentiation of human TH-17 cells is independent of TGF- and thus differs fundamentally from that in mice. We show here that TGF-, IL-1 and IL-6, IL-21 or IL-23 in serum-free conditions were necessary and sufficient to induce IL-17 expression in naive human CD4+ T cells from cord blood. TGF- upregulated RORt expression but simultaneously inhibited its ability to induce IL-17 expression. Inflammatory cytokines relieved this inhibition and increased RORt-directed IL-17 expression. Other gene products detected in TH-17 cells after RORt induction included the chemokine receptor CCR6, the IL-23 receptor, IL-17F and IL-26. Our studies identify RORt as having a central function in the differentiation of human TH-17 cells from naive CD4+ T cells and suggest that similar cytokine pathways are involved in this process in mice and humans.
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
- Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA.
- Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA.
- Department of Pathology, New York University School of Medicine, New York, New York 10016, USA.
Correspondence to: Dan R Littman1,2,3,4 e-mail: littman@saturn.med.nyu.edu
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