RORC2 is involved in T cell polarization through interaction with the FOXP3 promoter.
The process of Th cell differentiation toward polarized effector T cells tailors specific immunity against invading pathogens while allowing tolerance against commensal microorganisms, harmless allergens, or autologous Ags. Identification of the mechanisms underlying this polarization process is therefore central to understand how the immune system confers immunity and tolerance. The present study demonstrates that retinoic acid receptor-related orphan receptor C2 (RORC2), a key transcription factor in Th17 cell development, inhibits FOXP3 expression in human T cells. Although overexpression of RORC2 in naive T cells reduces levels of FOXP3, small interfering RNA-mediated knockdown of RORC2 enhances its expression. RORC2 mediates this inhibition at least partially by binding to two out of four ROR-responsive elements on the FOXP3 promoter. Knockdown of RORC2 promotes high FOXP3 levels and decreased expression of proinflammatory cytokines beta form of pro-IL-1, IL-6, IL-17A, IFN-gamma, and TNF-alpha in differentiating naive T cells, suggesting that the role of RORC2 in Th17 cell development involves not only induction of Th17-characteristic genes, but also suppression of regulatory T cell-specific programs. Together, this study identifies RORC2 as a polarizing factor in transcriptional cross-regulation and provides novel viewpoints on the control of immune tolerance versus effector immune responses.
Burgler
Simone
S
Swiss Institute of Allergy and Asthma Research, Davos, Switzerland.
Mantel
Pierre-Yves
PY
Bassin
Claudio
C
Ouaked
Nadia
N
Akdis
Cezmi A
CA
Schmidt-Weber
Carsten B
CB
D001483:Base Sequence; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002469:Cell Separation; D017124:Conserved Sequence; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics* / Q000276:immunology; D047468:Immunoprecipitation; D008969:Molecular Sequence Data; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human