The Journal of Experimental Medicine
Aegean Conferences: 2009 Conferences
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Published 2 September 2003. doi:10.1084/jem.20021358
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© Rockefeller University Press, 0022-1007/2003/9/809 $5.00
The Journal of Experimental Medicine, Volume 198, Number 5, 809-821

Impaired T Cell Death and Lupus-like Autoimmunity in T Cell–specific Adapter Protein–deficient Mice

Jorn Drappa1, Lynn A. Kamen1,2, Elena Chan1, Maria Georgiev1, Dalit Ashany1, Francesc Marti1,2 and Philip D. King1,2

1 Research Division, Hospital for Special Surgery, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, NY 10021
2 Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109

Address correspondence to Philip D. King, University of Michigan Medical School, Department of Microbiology and Immunology, 6606 Medical Science Building II, Ann Arbor, MI 48109. Phone: (734) 615-9073; Fax: (734) 764-3562; email: kingp{at}umich.edu

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 autoantibodies 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.

Key Words: apoptosis • autoimmunity • T lymphocyte • signal transduction • glomerulonephritis


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