title: T cell receptor/CARMA1/NF-κB signaling controls T-helper (Th) 17 differentiation.
abstract: IL-17-producing CD4 T cells play a key role in immune responses against extracellular bacteria and autoimmunity. Nuclear factor κB (NF-κB) is required for T-cell activation and selected effector functions, but its role in Th17 differentiation is controversial. Using genetic mouse models that impede T-cell-NF-κB signaling either downstream of the T-cell receptor (TCR) or of IκB kinase β (IKKβ), we demonstrate that NF-κB signaling controls not only survival and proliferation of activated T cells, but, if cell survival and cell-cycle progression are enabled, has an additional role in promoting completion of Th17 differentiation. CARD-containing MAGUK protein 1 (CARMA1), an adapter required for TCR/NF-κB signaling, was necessary for acquisition of IL-17A, IL-17F, IL-21, IL-22, IL-23R, and CCR6 expression in T cells cultured under Th17 conditions. In proliferating cells, lack of CARMA1 selectively prevented Th17, but not Th1 or Th2 differentiation, in a cell-intrinsic manner. Consistent with these data, CARMA1-KO mice were resistant to experimental autoimmune encephalomyelitis. Surprisingly, transcription factors essential for Th17 differentiation such as RORγt, AHR, and IRF4 were normally induced in CARMA1-KO T cells activated under Th17 conditions, suggesting that the Th17 differentiation program was initiated normally. Instead, chromatin loci of Th17 effector molecules failed to acquire an open conformation in CARMA1-KO T cells. Our results demonstrate that TCR/CARMA1/NF-κB controls completion of Th17 differentiation by enabling chromatin accessibility of Th17 effector molecule loci.
authors.affiliation: Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA. lmoliner@medicine.bsd.uchicago.edu
authors.forename: Luciana L
authors.initials: LL
authors.lastname: Molinero
authors.forename: Alan
authors.initials: A
authors.lastname: Cubre
authors.forename: Carolina
authors.initials: C
authors.lastname: Mora-Solano
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Maria-Luisa
authors.initials: ML
authors.lastname: Alegre
mesh_terms: D000818:Animals; D053468:CARD Signaling Adaptor Proteins / Q000172:deficiency / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology*; D002843:Chromatin / Q000378:metabolism; D045142:Cross-Priming / Q000276:immunology; D005260:Female; D056426:Genetic Loci / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D053468:CARD Signaling Adaptor Proteins; C496467:Card11 protein, mouse; D002843:Chromatin; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D014157:Transcription Factors; D048056:Mitogen-Activated Protein Kinase 9