Impaired T cell death and lupus-like autoimmunity in T cell-specific adapter protein-deficient mice.
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.
Drappa
Jorn
J
Research Division, Hospital for Special Surgery, Weill Medical College and Graduate School of Medical Sciences, Cornell University, New York, NY 10021, USA.
Kamen
Lynn A
LA
Chan
Elena
E
Georgiev
Maria
M
Ashany
Dalit
D
Marti
Francesc
F
King
Philip D
PD
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D016923:Cell Death; D004195:Disease Models, Animal; D006942:Hypergammaglobulinemia / Q000235:genetics / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood / Q000145:classification; D007075:Immunoglobulin M / Q000097:blood; D007376:Interleukin-2 / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007376:Interleukin-2; C405691:SH2D2A protein, human