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.