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-FLIPL) is required for proliferation and effector T-cell development. However, the role of c-FLIPL in triggering autoimmunity has not been carefully analyzed. We now report that c-FLIPL 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-FLIPL overexpression inhibits the ζ 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-FLIPL as a susceptibility factor under the influence of epistatic modifiers for the development of autoimmunity.
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Abbreviations
- Ab:
-
antibody
- B6:
-
C57BL/6
- BrdU:
-
5-bromo-2-deoxyuridine
- c-FLIP:
-
cellular FLICE-inhibitory protein
- CFSE:
-
carboxyfluorescein succinimidyl ester
- DC:
-
dendritic cells
- DN:
-
double negative
- DP:
-
double positive
- ERK:
-
excellular signal-regulated kinase
- JNK:
-
c-Jun-NH2-terminal kinase
- LAT:
-
the Linker for activation of T cells
- MAPK:
-
mitogen-activated protein kinase
- MMTV:
-
mouse mammary tumor virus
- NLC:
-
non-Tg littermate controls
- OVA:
-
ovalbumin
- PLC-γ1:
-
phospholipase C-gamma-1
- SLE:
-
systemic lupus erythematosus
- SLP-76:
-
SH2-domain-containing leukocyte protein of 76 kDa
- SP:
-
single positive
- Tg:
-
transgenic
- TCR:
-
T-cell receptor
- VSAg:
-
viral super-antigen
- ZAP-70:
-
ζ chain-associated protein tyrosine kinase of 70 kDa
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Acknowledgements
We thank Drs. Marcus Peter and Yang-Xin Fu for critical reading of the paper and discussion. This work is in part supported by a novel research grant from the Lupus Research Institute (to JZ) and a start-up fund from the University of Chicago. Additional support was provided by grants from the National Institutes of Health (NIH) (R01 AR049775 to JZ and DK055357 to RJQ) and from the American Heart Association (09GRNT2010084 to JZ). JZ was supported by a NIH independent scientist award (K02 AR 049047), and is an American Lung Association Career Investigator.
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Qiao, G., Li, Z., Minto, A. et al. Altered thymic selection by overexpressing cellular FLICE inhibitory protein in T cells causes lupus-like syndrome in a BALB/c but not C57BL/6 strain. Cell Death Differ 17, 522–533 (2010). https://doi.org/10.1038/cdd.2009.143
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DOI: https://doi.org/10.1038/cdd.2009.143
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