T cell receptor/CARMA1/NF-κB signaling controls T-helper (Th) 17 differentiation.
In: Proceedings of the National Academy of Sciences of the United States of America, Jg. 109 (2012-11-06), Heft 45, S. 18529-34
Online
academicJournal
Zugriff:
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.
Titel: |
T cell receptor/CARMA1/NF-κB signaling controls T-helper (Th) 17 differentiation.
|
---|---|
Autor/in / Beteiligte Person: | Molinero, LL ; Cubre, A ; Mora-Solano, C ; Wang, Y ; Alegre, ML |
Link: | |
Zeitschrift: | Proceedings of the National Academy of Sciences of the United States of America, Jg. 109 (2012-11-06), Heft 45, S. 18529-34 |
Veröffentlichung: | Washington, DC : National Academy of Sciences, 2012 |
Medientyp: | academicJournal |
ISSN: | 1091-6490 (electronic) |
DOI: | 10.1073/pnas.1204557109 |
Schlagwort: |
|
Sonstiges: |
|