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Enhanced T Cell Apoptosis within Drak2-Deficient Mice Promotes Resistance to Autoimmunity¹

Center for Immunology and Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697

Clonal expansion of T cells is vital to adaptive immunity, yet this process must be tightly controlled to prevent autoimmune disease. The serine/threonine kinase death-associated protein kinase-related apoptosis-inducing kinase 2 (DRAK2) is a negative regulator of TCR signaling and sets the threshold for the activation of naive and memory T cells and selected thymocytes. Despite enhanced T cell activation, Drak2^–/– mice are resistant to experimental autoimmune encephalomyelitis, an autoimmune demyelinating disease that resembles multiple sclerosis. However, the basis for this autoimmune resistance is currently unknown. In this study, we show that, in the absence of DRAK2 signaling, T cells require greater tonic signaling for maintenance during clonal expansion. Following stimulation, Drak2^–/– T cells were more sensitive to an intrinsic form of apoptosis that was prevented by CD28 ligation, homeostatic cytokines, or enforced Bcl-x_L expression. T cell-specific Bcl-x_L expression also restored the susceptibility of Drak2^–/– mice to experimental autoimmune encephalomyelitis and enhanced thymic positive selection. These findings demonstrate that DRAK2 is selectively important for T cell survival and highlight the potential that DRAK2 blockade may lead to permanent autoimmune T cell destruction via intrinsic apoptosis pathways.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (RO1-A63419 and RO1-AI50506 to C.M.W., and T32-AI60573 to S.J.R.), and by fellowships from the Arthritis National Research Foundation (to C.M.W. and M.G.).

² S.J.R. and J.B.H. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Craig M. Walsh, Center for Immunology and Department of Molecular Biology and Biochemistry, 3215 McGaugh Hall, University of California, Irvine, CA 92697. E-mail address: cwalsh{at}uci.edu

⁴ Abbreviations used in this paper: AICD, activation-induced cell death; ACAD, activated cell autonomous death; Csp1, calcipressin-1; DAPK, death-associated protein kinase; DRAK2, DAPK-related apoptosis-inducing kinase 2; EAE, experimental autoimmune encephalomyelitis; FasL, Fas ligand; LCMV, lymphocytic choriomeningitis virus; MHV, mouse hepatitis virus; MOG, myelin oligodendrocyte; SEB, staphylococcal enterotoxin B; Tg, transgenic.

⁵ The online version of this article contains supplemental material.

This article has been cited by other articles:

				M. Gatzka, R. H. Newton, and C. M. Walsh Altered Thymic Selection and Increased Autoimmunity Caused by Ectopic Expression of DRAK2 during T Cell Development J. Immunol., July 1, 2009; 183(1): 285 - 297. [Abstract] [Full Text] [PDF]