Role of cFLIP in the initiation and maintenance of the germinal center response (84.18)

Abstract

Abstract During a T cell-dependent immune response, B cells are activated and accumulate in germinal centers where they proliferate, undergo somatic hypermutation, and stringent clonal selection. These events are essential to the production of high affinity antibody responses and long-lived memory B cell populations. Apoptotic pathways are believed to play a pivotal role in regulating the expansion of activated B cells and negative selection events operative in germinal centers. Increased levels of the death receptor Fas on germinal center B cells should make them highly sensitive to Fas-induced cell death. However, previous studies have suggested a role for increased levels of cellular FLICE-inhibitory protein (cFLIP) in preventing Fas-mediated apoptosis in germinal center B cells. Therefore, regulation of cFLIP expression may important to the maturation of the immune response and the maintenance of peripheral tolerance. In the present study, we utilize mice with a B cell-specific deletion of cFLIP to assess its requirement during a T-dependent immune response. Analysis of bone marrow and splenic B cell populations in these mice indicates that there is no apparent maturation defect, despite a mild B cell-specific lymphopenia. However, data from immunization studies with various T-dependent antigens suggests an important role for cFLIP expression in the expansion of antigen-specific B cells and their participation in the germinal center response. This work is supported by T32CA09683 to F.C. and AI038965 to T.M.