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.
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1 September 2003
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September 02 2003
Impaired T Cell Death and Lupus-like Autoimmunity in T Cell–specific Adapter Protein–deficient Mice
Jorn Drappa,
Jorn Drappa
1Research Division, Hospital for Special Surgery, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, NY 10021
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Lynn A. Kamen,
Lynn A. Kamen
1Research Division, Hospital for Special Surgery, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, NY 10021
2Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109
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Elena Chan,
Elena Chan
1Research Division, Hospital for Special Surgery, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, NY 10021
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Maria Georgiev,
Maria Georgiev
1Research Division, Hospital for Special Surgery, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, NY 10021
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Dalit Ashany,
Dalit Ashany
1Research Division, Hospital for Special Surgery, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, NY 10021
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Francesc Marti,
Francesc Marti
1Research Division, Hospital for Special Surgery, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, NY 10021
2Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109
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Philip D. King
Philip D. King
1Research Division, Hospital for Special Surgery, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, NY 10021
2Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109
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Jorn Drappa
1Research Division, Hospital for Special Surgery, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, NY 10021
Lynn A. Kamen
1Research Division, Hospital for Special Surgery, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, NY 10021
2Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109
Elena Chan
1Research Division, Hospital for Special Surgery, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, NY 10021
Maria Georgiev
1Research Division, Hospital for Special Surgery, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, NY 10021
Dalit Ashany
1Research Division, Hospital for Special Surgery, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, NY 10021
Francesc Marti
1Research Division, Hospital for Special Surgery, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, NY 10021
2Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109
Philip D. King
1Research Division, Hospital for Special Surgery, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, NY 10021
2Department 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: [email protected]
Abbreviations used in this paper: ANA, antinuclear antibodies; ds, double stranded; GAMIgG, goat anti–mouse IgG; H&E, hematoxylin and eosin; SEB, staphylococcal enterotoxin B; ss, single stranded; TSAd, T cell–specific adapter protein.
J. Drappa and L.A. Kamen contributed equally to this work.
The online version of this article contains supplemental material.
Received:
August 06 2002
Revision Received:
July 23 2003
Accepted:
July 23 2003
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2003
J Exp Med (2003) 198 (5): 809–821.
Article history
Received:
August 06 2002
Revision Received:
July 23 2003
Accepted:
July 23 2003
Citation
Jorn Drappa, Lynn A. Kamen, Elena Chan, Maria Georgiev, Dalit Ashany, Francesc Marti, Philip D. King; Impaired T Cell Death and Lupus-like Autoimmunity in T Cell–specific Adapter Protein–deficient Mice . J Exp Med 1 September 2003; 198 (5): 809–821. doi: https://doi.org/10.1084/jem.20021358
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