Differential dependence of CD4⁺CD25⁺ regulatory and natural killer-like T cells on signals leading to NF-κB activation

Natural killer-like (NK) T, regulatory T (TR), and memory type T cells display surface phenotypes reminiscent of activated T cells. Previously, we reported that the generation of T_R cells and, to a lesser extent, of memory type T cells, depends on IκB kinase 2. Here, we show that T cell-specific ablation of IκB kinase 2, in addition, completely precludes NKT cell development. T cell antigen receptor (TCR)-induced signals to activate NF-κB are essential for mature T cell activation, leading us to hypothesize that this pathway could play an important role in the generation of the antigen-driven T cell subsets comprising T_R, memory type T, and NKT cells. TCR-mediated NF-κB activation critically depends on Bcl10 and PKCθ. By using mice deficient for these proteins, we demonstrate that the generation of T_R and, to a lesser extent, of memory type T cells, depends on Bcl10 and PKCθ, and therefore, most likely on NF-κB activation initiated by TCR engagement. NKT cells, on the other hand, require PKCθ for thymic development, whereas absence of Bcl10 leads primarily to the reduction of peripheral NKT cell numbers.