T Helper 17 Lineage Differentiation Is Programmed by Orphan Nuclear Receptors RORα and RORγ
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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.
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Higher frequency of cells producing IL-21 and IL-17a was observed within cytotoxic cells, probably due to active Rora regulon.
“We also observed higher frequency of cells producing IL-21 and IL-17a within cytotoxic cells (fig. S7A), probably due to the active Rora regulon [Fig. 5B; (49)].”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [49]
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- Authors
- Yang, X. O., Pappu, B. P., Nurieva, R., Akimzhanov, A., Kang, H. S., Chung, Y., Ma, L., Shah, B., Panopoulos, A. D., Schluns, K. S., Watowich, S. S., Tian, Q., Jetten, A. M., & Dong, C.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- National Institutes of Health (US)
- Institute for Systems Biology (US)
- Corresponding author
- Dong, Chen
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2008-01
- Volume
- 28
- Issue
- 1
- Pages
- 29-39
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC2587175
- OpenAlex
- W2091451666
- Cited by
- 1,605
- References
- 40
- Citations by year
- 2026: 27 · 2025: 47 · 2024: 42 · 2023: 54 · 2022: 72 · 2021: 83 · 2020: 86 · 2019: 81 · 2018: 70 · 2017: 74 · 2016: 96 · 2015: 103 · 2014: 100 · 2013: 101 · 2012: 109
- FWCI
- 63.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2024 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5u19ai071130-05)
- National Institute of Allergy and Infectious Diseases (U19-AI071130)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR-050772, R01AR050772)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Th17 cells, T helper cell differentiation, RORα, RORγ, orphan nuclear receptor, lineage-specific transcription factors, IL-17, IL-17F, TGF-beta, interleukin-6, STAT3 signaling, experimental autoimmune encephalomyelitis, tissue inflammation
- MeSH terms
- Animals, Cell Differentiation, Encephalomyelitis, Autoimmune, Experimental, Female, T-Lymphocytes, Helper-Inducer, Mice, Mutant Strains, Receptors, Thyroid Hormone, Trans-Activators, T-Lymphocyte Subsets, Receptors, Cytoplasmic and Nuclear, Receptors, Retinoic Acid, Cell Lineage, Reverse Transcriptase Polymerase Chain Reaction, Interleukin-17, Electrophoretic Mobility Shift Assay, Mice, Nuclear Receptor Subfamily 1, Group F, Member 1, Nuclear Receptor Subfamily 1, Group F, Member 3
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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