IL-21 and TGF-beta are required for differentiation of human T(H)17 cells.
The recent discovery of CD4(+) T cells characterized by secretion of interleukin (IL)-17 (T(H)17 cells) and the naturally occurring regulatory FOXP3(+) CD4 T cell (nT(reg)) has had a major impact on our understanding of immune processes not readily explained by the T(H)1/T(H)2 paradigm. T(H)17 and nT(reg) cells have been implicated in the pathogenesis of human autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis. Our recent data and the work of others demonstrated that transforming growth factor-beta (TGF-beta) and IL-6 are responsible for the differentiation of naive mouse T cells into T(H)17 cells, and it has been proposed that IL-23 may have a critical role in stabilization of the T(H)17 phenotype. A second pathway has been discovered in which a combination of TGF-beta and IL-21 is capable of inducing differentiation of mouse T(H)17 cells in the absence of IL-6 (refs 6-8). However, TGF-beta and IL-6 are not capable of differentiating human T(H)17 cells and it has been suggested that TGF-beta may in fact suppress the generation of human T(H)17 cells. Instead, it has been recently shown that the cytokines IL-1beta, IL-6 and IL-23 are capable of driving IL-17 secretion in short-term CD4(+) T cell lines isolated from human peripheral blood, although the factors required for differentiation of naive human CD4 to T(H)17 cells are still unknown. Here we confirm that whereas IL-1beta and IL-6 induce IL-17A secretion from human central memory CD4(+) T cells, TGF-beta and IL-21 uniquely promote the differentiation of human naive CD4(+) T cells into T(H)17 cells accompanied by expression of the transcription factor RORC2. These data will allow the investigation of this new population of T(H)17 cells in human inflammatory disease.
Yang
Li
L
Division of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Anderson
David E
DE
Baecher-Allan
Clare
C
Hastings
William D
WD
Bettelli
Estelle
E
Oukka
Mohamed
M
Kuchroo
Vijay K
VK
Hafler
David A
DA
D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D000098546:Interleukin-21
D020381:Interleukin-17; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; C539901:Rorc protein, mouse; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D000098546:Interleukin-21