T cell receptor/CARMA1/NF-κB signaling controls T-helper (Th) 17 differentiation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-11, Vol.109 (45), p.18529-18534
• Main Authors: Molinero, Luciana L, Cubre, Alan, Mora-Solano, Carolina, Wang, Ying, Alegre, Maria-Luisa
• Format: Article
• Language: English
• Subjects: animal models; Animals; autoimmunity; bacteria; Biological Sciences; CARD Signaling Adaptor Proteins - deficiency; CARD Signaling Adaptor Proteins - metabolism; CCR6 receptor; CD4-positive T-lymphocytes; cell cycle; Cell Differentiation - immunology; cell viability; Cellular differentiation; Chromatin; Chromatin - metabolism; Cross-Priming - immunology; Cultured cells; Cytokines; encephalitis; Female; Genetic loci; Genetic Loci - genetics; immune response; interleukin-17; interleukin-21; loci; Messenger RNA; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 9 - metabolism; Molecules; NF-kappa B - metabolism; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Signal Transduction - immunology; STAT3 Transcription Factor - metabolism; STAT5 Transcription Factor - metabolism; T cell antigen receptors; T lymphocytes; Th17 Cells - cytology; Th17 Cells - enzymology; Th17 Cells - immunology; transcription factor NF-kappa B; Transcription factors; Transcription Factors - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1204557109

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.