Altered Thymic Selection by Over-Expressing Cellular FLICE Inhibitory Protein in T Cells Causes Lupus-like Syndrome in BALB/c but not C57BL/6 Strain

Cellular FLICE inhibitory protein (c-FLIP) is an endogenous inhibitor of the caspase-8 pro-apoptotic signaling pathway downstream of death receptors. Recent evidence indicates that the long form of c-FLIP (c-FLIPL) is required for proliferation and effector T cell development. However, the role of c-FLIPL in triggering autoimmunity has not been carefully investigated. We now report that c-FLIPL transgenic (Tg) mice develop splenomegaly, lymphadenopathy, multi-organ infiltration, high titers of autoantibodies, and proliferative glomerulonephritis with immune complex deposition in a strain-dependent fashion. The development of autoimmunity requires CD4+ T cells and may result from impaired thymic selection. At the molecular level, c-FLIPL over-expression inhibits the ZAP-70 activation, thus impairing the signaling pathway derived from ZAP-70 required for thymic selection. Therefore, we have identified c-FLIPL as a susceptibility factor under the influence of epistatic modifiers for the development of autoimmunity