RelB regulates Th17 differentiation in a cell-intrinsic manner.

The role of the alternative NF-κB pathway is mainly attributed to the lymphoid organ formation and blood cancer. However, its involvement in lymphocyte differentiation is not clearly defined. Recently, we have shown that uncontrolled activation of alternative NF-κB in mice lacking the NF-κB inhibitory protein p100 (p100 mice) hinders plasmablast proliferation and diminishes T cell independent responses. Here we show that hyperactivation of this pathway leads to a cell-intrinsic T cell defects. p100-deficient T helper cells displayed both an activation and a proliferation defect in vitro. In addition, memory T cell formation was impaired in vivo. Moreover, p100 T cells failed to polarize into T helper 17 cells. This phenotype was dependent on increased RelB activation and suboptimal RORγt expression. Thus, our results demonstrate that RelB acts as a negative regulator of T cell activation and Th17 development. Targeting this pathway therefore could be beneficial in Th17-mediated pathologies.