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

G Qiao; Z Li; A W Minto; J Shia; L Yang; L Bao; J Tschopp; J-X Gao; J Wang; R J Quigg; J Zhang

doi:10.1038/cdd.2009.143

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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

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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

G Qiao, Z Li, A W Minto, J Shia, L Yang, L Bao, J Tschopp, J-X Gao, J Wang, R J Quigg, …

Cell death and differentiation, Vol.17(3), pp.522-533

03/2010

DOI: 10.1038/cdd.2009.143

PMCID: PMC2822025

PMID: 19816511

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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.

Phenotype

T-Lymphocyte Subsets - immunology

Autoantibodies - metabolism

Cell Proliferation

T-Lymphocyte Subsets - cytology

Dendritic Cells - immunology

Humans

Mice, Inbred BALB C - immunology

Mice, Inbred C57BL - immunology

Lupus Erythematosus, Systemic - immunology

ZAP-70 Protein-Tyrosine Kinase - metabolism

Transgenes

CASP8 and FADD-Like Apoptosis Regulating Protein - metabolism

Cytokines - metabolism

CASP8 and FADD-Like Apoptosis Regulating Protein - genetics

Lymphocyte Activation

Thymus Gland - cytology

Mice, Transgenic

Animals

B-Lymphocytes - immunology

T-Lymphocytes - cytology

T-Lymphocytes - immunology

Thymus Gland - immunology

Mice

Apoptosis - physiology

Lupus Erythematosus, Systemic - physiopathology

Lupus Erythematosus, Systemic - pathology

Details

Title: Subtitle: 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
Creators: G Qiao - Section of Nephrology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA
Z Li
A W Minto
J Shia
L Yang
L Bao
J Tschopp
J-X Gao
J Wang
R J Quigg
J Zhang
Resource Type: Journal article
Publication Details: Cell death and differentiation, Vol.17(3), pp.522-533
Publisher: England
DOI: 10.1038/cdd.2009.143
PMID: 19816511
PMCID: PMC2822025
ISSN: 1350-9047
eISSN: 1476-5403
Grant note: R01 AR049775-04 / NIAMS NIH HHS R01 AR049775 / NIAMS NIH HHS R01 AR049775-05 / NIAMS NIH HHS DK055357 / NIDDK NIH HHS R01 AR049775-03 / NIAMS NIH HHS K02 AR 049047 / NIAMS NIH HHS K02 AR049047 / NIAMS NIH HHS
Language: English
Date published: 03/2010
Academic Unit: Pathology
Record Identifier: 9984047786702771

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