| First Author | Molinero LL | Year | 2012 |
| Journal | Proc Natl Acad Sci U S A | Volume | 109 |
| Issue | 45 | Pages | 18529-34 |
| PubMed ID | 23091043 | Mgi Jnum | J:191230 |
| Mgi Id | MGI:5461275 | Doi | 10.1073/pnas.1204557109 |
| Citation | Molinero LL, et al. (2012) T cell receptor/CARMA1/NF-kappaB signaling controls T-helper (Th) 17 differentiation. Proc Natl Acad Sci U S A 109(45):18529-34 |
| abstractText | IL-17-producing CD4 T cells play a key role in immune responses against extracellular bacteria and autoimmunity. Nuclear factor kappaB (NF-kappaB) 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-kappaB signaling either downstream of the T-cell receptor (TCR) or of IkappaB kinase beta (IKKbeta), we demonstrate that NF-kappaB 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-kappaB 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 RORgammat, 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-kappaB controls completion of Th17 differentiation by enabling chromatin accessibility of Th17 effector molecule loci. |
