Article

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
Source: PubMed

ABSTRACT

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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Available from: Jian Zhang, Aug 23, 2014
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    • "). To evaluate whether Cbl-b regulates Pten subcellular localization, we isolated the membrane and cytosolic fractions from WT and Cbl-b À/À T cells before and after TCR or TCR/CD28 stimulation (Qiao et al., 2010; Salojin et al., 1997). Although Pten was located in either the plasma membrane or cytoplasm of resting WT and Cbl-b À/À T cells, membrane-associated Pten was reduced in WT T cells upon TCR stimulation, and this process was heightened in the presence of CD28 costimulation (Figure 5A). "

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