Publikationsdatum:
2010-10-22
Beschreibung:
CD4(+) T-helper cells that selectively produce interleukin (IL)-17 (T(H)17), are critical for host defence and autoimmunity. Although crucial for T(H)17 cells in vivo, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-beta1 have been proposed to be the factors responsible for initiating specification. Here we show that T(H)17 differentiation can occur in the absence of TGF-beta signalling. Neither IL-6 nor IL-23 alone efficiently generated T(H)17 cells; however, these cytokines in combination with IL-1beta effectively induced IL-17 production in naive precursors, independently of TGF-beta. Epigenetic modification of the Il17a, Il17f and Rorc promoters proceeded without TGF-beta1, allowing the generation of cells that co-expressed RORgammat (encoded by Rorc) and T-bet. T-bet(+)RORgammat(+) T(H)17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred T(H)17 cells generated with IL-23 without TGF-beta1 were pathogenic in this disease model. These data indicate an alternative mode for T(H)17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore may have therapeutic implications.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108066/" 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/PMC3108066/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ghoreschi, Kamran -- Laurence, Arian -- Yang, Xiang-Ping -- Tato, Cristina M -- McGeachy, Mandy J -- Konkel, Joanne E -- Ramos, Haydee L -- Wei, Lai -- Davidson, Todd S -- Bouladoux, Nicolas -- Grainger, John R -- Chen, Qian -- Kanno, Yuka -- Watford, Wendy T -- Sun, Hong-Wei -- Eberl, Gerard -- Shevach, Ethan M -- Belkaid, Yasmine -- Cua, Daniel J -- Chen, Wanjun -- O'Shea, John J -- Z99 AR999999/Intramural NIH HHS/ -- England -- Nature. 2010 Oct 21;467(7318):967-71. doi: 10.1038/nature09447.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ghoreschik@mail.nih.gov〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20962846" target="_blank"〉PubMed〈/a〉
Schlagwort(e):
Animals
;
Autoimmune Diseases/immunology/pathology
;
Autoimmunity/immunology
;
Cell Differentiation/drug effects
;
Central Nervous System/pathology
;
Inflammation
;
Interleukin-10
;
Interleukin-17/secretion
;
Interleukin-1beta/immunology
;
Interleukin-23/immunology/pharmacology
;
Interleukin-6/immunology
;
Interleukin-9
;
Interleukins/biosynthesis
;
Mice
;
Mice, Inbred C57BL
;
Mucous Membrane/cytology/immunology
;
Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism
;
Receptors, Interleukin/metabolism
;
*Signal Transduction
;
Th17 Cells/drug effects/metabolism/*pathology
;
*Transforming Growth Factor beta
Print ISSN:
0028-0836
Digitale ISSN:
1476-4687
Thema:
Biologie
,
Chemie und Pharmazie
,
Medizin
,
Allgemeine Naturwissenschaft
,
Physik
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