A deficiency in Drak2 results in a T cell hypersensitivity and an unexpected resistance to autoimmunity.
DRAK2 is a member of the death-associated protein (DAP)-like family of serine/threonine kinases. Members of this family induce apoptosis in various cell types. DRAK2, in particular, is specifically expressed in T cells and B cells, and it is differentially regulated during T cell development. To determine whether DRAK2 regulates lymphocyte apoptosis, we produced Drak2(-/-) mice. Contrary to our expectations, Drak2(-/-) T cells did not demonstrate any defects in apoptosis or negative selection; however, T cells from Drak2(-/-) mice exhibited enhanced sensitivity to T cell receptor-mediated stimulation with a reduced requirement for costimulation. These results provide evidence that DRAK2 raises the threshold for T cell activation by negatively regulating signals through the TCR. In contrast to other models of T cell hypersensitivity, Drak2(-/-) mice were remarkably resistant to experimental autoimmune encephalomyelitis (EAE). These results expose a new pathway regulating T cell activation and highlight the intricacies of induced autoimmune disease.
McGargill
Maureen A
MA
Division of Biological Sciences, Department of Cellular and Molecular Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093 USA.
Wen
Ben G
BG
Walsh
Craig M
CM
Hedrick
Stephen M
SM
D000818:Animals; D017209:Apoptosis; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D007156:Immunologic Memory / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
D016207:Cytokines; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; C495197:Drak2 protein, mouse; D017346:Protein Serine-Threonine Kinases