TCR-CARMA1-NF-κB controls Th17 differentiation (152.4)

Abstract

Abstract IL-17 producing-CD4 T cells play a key role in immune responses against extracellular bacteria and autoimmunity. The transcription factor NF-kB is required for T cell activation and effector functions. Here, we investigated the role of T cell receptor (TCR)-mediated NF-kB in Th17 differentiation. In vitro, cells deficient in the adaptor molecule CARMA1, necessary for TCR-NF-kB signaling, did not differentiate towards a Th17 program, as shown by absence of IL-17A or IL-17F, IL-22, IL-21, IL-23R and CCR6. Consistently, CARMA1-deficient mice did not develop Th17-driven experimental autoimmune encephalomyelitis. CARMA1 selectively affected Th17 but not Th1 or Th2 differentiation in a cell intrinsic manner. While CARMA1 controls both NF-kB and JNK2 TCR-mediated activation, only NF-kB-impaired T cells (IkBaDN-Tg) had defective Th17 differentiation, confirming that Th17 differentiation requires intact TCR-CARMA1-NF-κB signaling. Despite impaired Th17 differentiation, CARMA1-deficient cells had intact IL-6 or TGFb signaling, as assessed by p-STAT3 and p-Smad2/3. Moreover, induction of transcription factors essential for Th17 differentiation such as RORgt, proceeded normally in CARMA1-deficient T cells. Notably, accessibility to the IL-17 locus was impaired in CARMA1-deficient cells. Our results demonstrate that TCR-CARMA1-NF-κB controls Th17 differentiation by enabling IL-17 locus accessibility. Targeting T cell NF-kB could be potentially used as therapy for autoimmune diseases.