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PMID: 18164222 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma.

Immunity ·Vol. 28 ·No. 1 ·2008-01-00 ·Pages 29-39

Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, Ma L, Shah B, Panopoulos AD, Schluns KS, Watowich SS, Tian Q, Jetten AM, Dong C

Abstract

T cell functional differentiation is mediated by lineage-specific transcription factors. T helper 17 (Th17) has been recently identified as a distinct Th lineage mediating tissue inflammation. Retinoic acid receptor-related orphan receptor gamma (ROR gamma) was shown to regulate Th17 differentiation; ROR gamma deficiency, however, did not completely abolish Th17 cytokine expression. Here, we report Th17 cells highly expressed another related nuclear receptor, ROR alpha, induced by transforming growth factor-beta and interleukin-6 (IL-6), which is dependent on signal transducer and activator of transcription 3. Overexpression of ROR alpha promoted Th17 differentiation, possibly through the conserved noncoding sequence 2 in Il17-Il17f locus. ROR alpha deficiency resulted in reduced IL-17 expression in vitro and in vivo. Furthermore, ROR alpha and ROR gamma coexpression synergistically led to greater Th17 differentiation. Double deficiencies in ROR alpha and ROR gamma globally impaired Th17 generation and completely protected mice against experimental autoimmune encephalomyelitis. Therefore, Th17 differentiation is directed by two lineage-specific nuclear receptors, ROR alpha and ROR gamma.

MeSH Terms
Animals Cell Differentiation/immunology Cell Lineage Electrophoretic Mobility Shift Assay Encephalomyelitis, Autoimmune, Experimental/immunology Female Interleukin-17/immunology,metabolism Mice Mice, Mutant Strains Nuclear Receptor Subfamily 1, Group F, Member 1 Nuclear Receptor Subfamily 1, Group F, Member 3 Receptors, Cytoplasmic and Nuclear/immunology,metabolism Receptors, Retinoic Acid/immunology,metabolism Receptors, Thyroid Hormone/immunology,metabolism Reverse Transcriptase Polymerase Chain Reaction T-Lymphocyte Subsets/cytology,immunology,metabolism T-Lymphocytes, Helper-Inducer/cytology,immunology,metabolism Trans-Activators/immunology,metabolism
Chemicals
Interleukin-17 Nuclear Receptor Subfamily 1, Group F, Member 1 Nuclear Receptor Subfamily 1, Group F, Member 3 Receptors, Cytoplasmic and Nuclear Receptors, Retinoic Acid Receptors, Thyroid Hormone Rorc protein, mouse Trans-Activators
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Yang Xuexian O
Department of Immunology, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Pappu Bhanu P
Nurieva Roza
Akimzhanov Askar
Kang Hong Soon
Chung Yeonseok
Ma Li
Shah Bhavin
Panopoulos Athanasia D
Schluns Kimberly S
Watowich Stephanie S
Tian Qiang
Jetten Anton M
Dong Chen
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Article Info
Journal
Immunity
Abbr.
Immunity
ISSN
1074-7613
DOI
10.1016/j.immuni.2007.11.016
Published
2008-01-00
Epub
2007-00-27
Pages
29-39
Language
English
Region
United States
NLM ID
9432918
PMCID
PMC2587175
Subset
IM
Grants
NIAID NIH HHS · U19 AI071130 · United States
NIAMS NIH HHS · R01 AR050772-05 · United States
NIAMS NIH HHS · R01 AR050772 · United States
NIAID NIH HHS · U19 AI071130-020006 · United States
NIAMS NIH HHS · AR050772 · United States
NIAMS NIH HHS · R01 AR050772-06 · United States
Corrections
CommentIn
PMID: 18199410
External Links
PubMed source DOI: 10.1016/j.immuni.2007.11.016 PMC Full Text View journal details
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