Constitutive expression of murine c-FLIP(R) 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.