An intrinsic role for the alternative NF-kappa B pathway in the T-cell response to virus (35.21)

Abstract

Abstract Regulation of NF-κB mediated signaling is controlled by two systems: the classical pathway and the alternative pathway. The alternative pathway refers to the processing of p100 to p52 regulated by an enzyme called NF-κB inducing kinase (NIK), and is essential for the normal function of B-cells, macrophages, and dendritic cells; however, little is known about its function in T-cells. Preliminary experiments determined that activation of the alternative pathway is necessary for CD4 mediated graft versus host disease. Based on those findings, we hypothesized that the broader T-cell response to a viral infection is also dependent on the alternative NF-κB pathway. Because of the dominant effects of deficiencies in the alternative pathway on B-cells, macrophages and dendritic cells, we could not discretely assess the T-cell response to pathogen in alternative pathway mutants. Therefore, we generated mixed bone marrow (BM) chimeras using BM from wild-type mice and alymphoplasia (aly) mice that lack a functional NIK protein or BM from p100 knockout mice. In these chimeras, 15-20% of the T-cells, less than 2% of the B-cells and less than 2% surveyed myeloid cells, possessed the mutant genotype. This allowed us to assess the function of T-cells lacking the alternative pathway in an otherwise normal immune system. Chimeras were infected with lymphocytic choriomeningitis virus (LCMV) and the immune response was analyzed 8 days post-infection. The percent of responding CD8 and CD4 T-cells was significantly reduced among aly/aly and p100-/- populations compared to wild-type cells, as measured by the percent of IFNγ positive cells following ex vivo stimulation with LCMV peptides and activation marker expression. These data demonstrate a T-cell intrinsic role for the alternative NF-κB pathway in the immune response to a viral infection.