Impaired T cell death and lupus-like autoimmunity in T cell-specific adapter protein-deficient mice

被引:57
作者
Drappa, J
Kamen, LA
Chan, E
Georgiev, M
Ashany, D
Marti, F
King, PD
机构
[1] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA
[2] Cornell Univ, Div Res, Hosp Special Surg, Weill Med Coll, New York, NY 10021 USA
[3] Cornell Univ, Grad Sch Med Sci, Hosp Special Surg, Weill Med Coll, New York, NY 10021 USA
关键词
apoptosis; autoimmunity; T lymphcyte; signal transduction; glomerulonephritis;
D O I
10.1084/jem.20021358
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
T cell-specific adaptor protein (TSAd) is a T lineage-restricted signaling adaptor molecule that is thought to participate in the assembly of intracellular signaling complexes in T cells. Previous studies of TSAd-deficient mice have revealed a role for TSAd in the induction of T cell interleukin 2 secretion and proliferation. We now show that TSAd-deficient mice are susceptible to lupus-like autoimmune disease. On the nonautoimmune-prone C57BL/6 genetic background, TSAd deficiency results in hypergammaglobulinemia that affects all immunoglobulin (Ig)G subclasses. Older C57BL/6 TSAd-deficient mice (1 yr of age) accumulate large numbers of activated T and B Cells in spleen, produce antibodies against a variety of self-targets including single stranded (ss) and double stranded (ds) DNA, and, in addition, develop glomerulonephritis. We further show that immunization of younger C57BL/6 TSAd-deficient mice (at age 2 mo) with pristane, a recognized nonspecific inflammatory trigger of lupus, results in more severe glomerulonephritis compared with C57BL/6 controls and the production of high titer ss and ds DNA antibodies of the IgG subclass that are not normally produced by C57BL/6 mice in this model. The development of autoimmunity in TSAd-deficient mice is associated with defective T cell death in vivo. These findings illustrate the role of TSAd as a critical regulator of T cell death whose absence promotes systemic autoimmunity.
引用
收藏
页码:809 / 821
页数:13
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