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Drak2 Regulates the Survival of Activated T Cells and Is Required for Organ-Specific Autoimmune Disease¹

Maureen A. McGargill^2,*, Carmen Choy^*, Ben G. Wen and Stephen M. Hedrick^3,*

^* Molecular Biology Section, Division of Biological Sciences, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093; and Department of Pharmacology, Genomics Institute of Novartis Research Foundation, San Diego, CA 92121

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.

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 National Institutes of Health Grant AI53091-01 and Juvenile Diabetes Research Foundation Grant 2-2007-105.

² Current address: St. Jude Children’s Research Hospital, Department of Immunology, Memphis, TN 38105.

³ Address correspondence and reprint requests to Dr. Stephen M. Hedrick, Molecular Biology Section, Division of Biological Sciences, Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093. E-mail address: shedrick{at}ucsd.edu

⁴ Abbreviations used in this paper: DAPK, death-associated protein kinase; EAE, experimental autoimmune encephalomyelitis; LCMV, lymphocytic choriomeningitis virus; MBP, myelin basic protein; MHV, mouse hepatitis virus; MOG, myelin oligodendrocyte glycoprotein; SLE, systemic lupus erythematosus.