Publication Date:
2008-03-28
Description:
T helper cells that produce IL-17 (T(H)17 cells) promote autoimmunity in mice and have been implicated in the pathogenesis of human inflammatory diseases. At mucosal surfaces, T(H)17 cells are thought to protect the host from infection, whereas regulatory T (T(reg)) cells control immune responses and inflammation triggered by the resident microflora. Differentiation of both cell types requires transforming growth factor-beta (TGF-beta), but depends on distinct transcription factors: RORgammat (encoded by Rorc(gammat)) for T(H)17 cells and Foxp3 for T(reg) cells. How TGF-beta regulates the differentiation of T cells with opposing activities has been perplexing. Here we demonstrate that, together with pro-inflammatory cytokines, TGF-beta orchestrates T(H)17 cell differentiation in a concentration-dependent manner. At low concentrations, TGF-beta synergizes with interleukin (IL)-6 and IL-21 (refs 9-11) to promote IL-23 receptor (Il23r) expression, favouring T(H)17 cell differentiation. High concentrations of TGF-beta repress IL23r expression and favour Foxp3+ T(reg) cells. RORgammat and Foxp3 are co-expressed in naive CD4+ T cells exposed to TGF-beta and in a subset of T cells in the small intestinal lamina propria of the mouse. In vitro, TGF-beta-induced Foxp3 inhibits RORgammat function, at least in part through their interaction. Accordingly, lamina propria T cells that co-express both transcription factors produce less IL-17 (also known as IL-17a) than those that express RORgammat alone. IL-6, IL-21 and IL-23 relieve Foxp3-mediated inhibition of RORgammat, thereby promoting T(H)17 cell differentiation. Therefore, the decision of antigen-stimulated cells to differentiate into either T(H)17 or T(reg) cells depends on the cytokine-regulated balance of RORgammat and Foxp3.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597437/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597437/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Liang -- Lopes, Jared E -- Chong, Mark M W -- Ivanov, Ivaylo I -- Min, Roy -- Victora, Gabriel D -- Shen, Yuelei -- Du, Jianguang -- Rubtsov, Yuri P -- Rudensky, Alexander Y -- Ziegler, Steven F -- Littman, Dan R -- AI48779/AI/NIAID NIH HHS/ -- R01 AI048779/AI/NIAID NIH HHS/ -- R01 AI048779-05/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 May 8;453(7192):236-40. doi: 10.1038/nature06878. Epub 2008 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18368049" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Differentiation/drug effects
;
Cell Line
;
Cells, Cultured
;
Forkhead Transcription Factors/genetics/*metabolism
;
Gene Expression Regulation/drug effects
;
Humans
;
Interleukin-17/biosynthesis/genetics/*metabolism
;
Mice
;
Mice, Inbred C57BL
;
Nuclear Receptor Subfamily 1, Group F, Member 3
;
Receptors, Interleukin/genetics/metabolism
;
Receptors, Retinoic Acid/*antagonists & inhibitors/genetics/metabolism
;
Receptors, Thyroid Hormone/*antagonists & inhibitors/genetics/metabolism
;
T-Lymphocytes, Helper-Inducer/*cytology/*drug effects/metabolism
;
Transforming Growth Factor beta/*pharmacology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
