Drak2 regulates the survival of activated T cells and is required for organ-specific autoimmune disease.
Drak2 is a serine/threonine kinase expressed in T and B cells. The absence of Drak2 renders T cells hypersensitive to suboptimal stimulation, yet Drak2(-/-) mice are enigmatically resistant to experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. We show in this study that Drak2(-/-) mice were also completely resistant to type 1 diabetes when bred to the NOD strain of mice that spontaneously develop autoimmune diabetes. However, there was not a generalized suppression of the immune system, because Drak2(-/-) mice remained susceptible to other models of autoimmunity. Adoptive transfer experiments revealed that resistance to disease was intrinsic to the T cells and was due to a loss of T cell survival under conditions of chronic autoimmune stimulation. Importantly, the absence of Drak2 did not alter the survival of naive T cells, memory T cells, or T cells responding to an acute viral infection. These experiments reveal a distinction between the immune response to persistent self-encoded molecules and transiently present infectious agents. We present a model whereby T cell survival depends on a balance of TCR and costimulatory signals to explain how the absence of Drak2 affects autoimmune disease without generalized suppression of the immune system.
McGargill
Maureen A
MA
Department of Cellular and Molecular Medicine, Division of Biological Sciences, Molecular Biology Section, University of California, San Diego, La Jolla, CA 92093, USA.
Choy
Carmen
C
Wen
Ben G
BG
Hedrick
Stephen M
SM
D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000276:immunology*; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000201:enzymology / Q000276:immunology*; D009928:Organ Specificity / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology*
C495197:Drak2 protein, mouse; D017346:Protein Serine-Threonine Kinases