The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat.
T(H)-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-beta (TGF-beta) and requires induction of the nuclear receptor RORgammat. It has been suggested that the differentiation of human T(H)-17 cells is independent of TGF-beta and thus differs fundamentally from that in mice. We show here that TGF-beta, IL-1beta 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-beta upregulated RORgammat expression but simultaneously inhibited its ability to induce IL-17 expression. Inflammatory cytokines relieved this inhibition and increased RORgammat-directed IL-17 expression. Other gene products detected in T(H)-17 cells after RORgammat induction included the chemokine receptor CCR6, the IL-23 receptor, IL-17F and IL-26. Our studies identify RORgammat as having a central function in the differentiation of human T(H)-17 cells from naive CD4+ T cells and suggest that similar cytokine pathways are involved in this process in mice and humans.
Manel
Nicolas
N
The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
Unutmaz
Derya
D
Littman
Dan R
DR
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
C440021:IL17F protein, human; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse; D016212:Transforming Growth Factor beta