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
Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.Cell death and differentiation (Impact Factor: 8.18). 10/2009; 17(3):522-33. DOI: 10.1038/cdd.2009.143
The cellular FLICE inhibitory protein (c-FLIP) is an endogenous inhibitor of the caspase-8 proapoptotic signaling pathway downstream of death receptors. Recent evidence indicates that the long form of c-FLIP (c-FLIP(L)) is required for proliferation and effector T-cell development. However, the role of c-FLIP(L) in triggering autoimmunity has not been carefully analyzed. We now report that c-FLIP(L) transgenic (Tg) mice develop splenomegaly, lymphadenopathy, multiorgan infiltration, high titers of auto-antibodies, and proliferative glomerulonephritis with immune complex deposition in a strain-dependent manner. The development of autoimmunity requires CD4(+) T cells and may result from impaired thymic selection. At the molecular level, c-FLIP(L) overexpression inhibits the zeta chain-associated protein tyrosine kinase of 70 kDa (ZAP-70) activation, thus impairing the signaling pathway derived from ZAP-70 required for thymic selection. Therefore, we have identified c-FLIP(L) as a susceptibility factor under the influence of epistatic modifiers for the development of autoimmunity.
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