The alternative NF-kappa B pathway is essential for OX40-induced CD4 T cell differentiation and effector function (47.19)

Abstract

Abstract Nuclear factor-kappa B (NF-κB) is an evolutionarily conserved signaling pathway that alerts the immune system to infection and danger. NF-κB can be divided broadly into two pathways-the canonical pathway regulated by IκB and the alternative pathway that depends on NF-κB inducing kinase (NIK) and IKKα. Mediators as divergent as pathogen-associated antigens, reactive oxygen species, UV light, and cytokines can activate the canonical NF-κB pathway. Activation of the alternative pathway seems to be limited to a subset of TNFRs, the best studied of which are LTβR, BAFFR, and CD40. Mice with lesions in the alternative NF-κB pathway have disorganized lymphoid structures and few peripheral B cells, but T cell responses in these mice have been less well-studied. Here, we show that the costimulatory TNFR, OX40 (CD134), activates the alternative NF-κB pathway in primary CD4 T cells. Activation of the alternative NF-κB pathway is necessary for OX40-induced differentiation and acquisition of effector function in vivo. Moreover, inability to activate the alternative NF-κB pathway rendered T cells unable to induce lethal GVHD. These results demonstrate a critical role for the alternative NF-κB pathway in CD4 T cell responses, and suggest that interventions targeting this pathway may have therapeutic potential. Supported by NIH R21 AI077032 (D.C.P.) and NIH T32 HL007781 (S.E.M.)