Constitutive expression of murine c-FLIPR causes autoimmunity in aged mice

Death receptor-mediated apoptosis is a key mechanism for the control of immune responses and dysregulation of this pathway may lead to autoimmunity. Cellular FLICE-inhibitory proteins (c-FLIPs) are known as inhibitors of death receptor-mediated apoptosis. The only short murine c-FLIP splice variant is c-FLIP_Raji (c-FLIP_R). To investigate the functional role of c-FLIP_R in the immune system, we used the vavFLIP_R mouse model constitutively expressing murine c-FLIP_R in all hematopoietic compartments. Lymphocytes from these mice are protected against CD95-mediated apoptosis and activation-induced cell death. Young vavFLIP_R mice display normal lymphocyte compartments, but the lymphocyte populations alter with age. We identified reduced levels of T cells and slightly higher levels of B cells in 1-year-old vavFLIP_R mice compared with wild-type (WT) littermates. Moreover, both B and T cells from aged vavFLIP_R animals show activated phenotypes. Sera from 1-year-old WT and transgenic animals were analysed for anti-nuclear antibodies. Notably, elevated titres of these autoantibodies were detected in vavFLIP_R sera. Furthermore, tissue damage in kidneys and lungs from aged vavFLIP_R animals was observed, indicating that vavFLIP_R mice develop a systemic lupus erythematosus-like phenotype with age. Taken together, these data suggest that c-FLIP_R is an important modulator of apoptosis and enforced expression leads to autoimmunity.