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Altered Thymic Selection and Increased Autoimmunity Caused by Ectopic Expression of DRAK2 during T Cell Development¹

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

Negative regulation of TCR signaling is an important mechanism enforcing immunological self-tolerance to prevent inappropriate activation of T cells and thus the development of autoimmune diseases. The lymphoid-restricted serine/threonine kinase death-associated protein-related apoptotic kinase-2 (DRAK2) raises the TCR activation threshold by targeting TCR-induced calcium mobilization in thymocytes and peripheral T cells and regulates positive thymic selection and peripheral T cell activation. Despite a hypersensitivity of peripheral drak2-deficient T cells, drak2-deficient mice are enigmatically resistant to induced autoimmunity in the model experimental autoimmune encephalomyelitis. To further evaluate the differential role of DRAK2 in central vs peripheral tolerance and to assess its impact on the development of autoimmune diseases, we have generated a transgenic (Tg) mouse strain ectopically expressing DRAK2 via the lck proximal promoter (1017-DRAK2 Tg mice). This transgene led to highest expression levels in double-positive thymocytes that are normally devoid of DRAK2. 1017-DRAK2 Tg mice displayed a reduction of single-positive CD4⁺ and CD8⁺ thymocytes in context with diminished negative selection in male HY TCR x 1017-DRAK2 Tg mice as well as peripheral T cell hypersensitivity, enhanced susceptibility to experimental autoimmune encephalomyelitis, and spontaneous autoimmunity. These findings suggest that alteration in thymocyte signaling thresholds impacts the sensitivity of peripheral T cell pools.

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 awards from the Arthritis National Research Foundation (ANRF-39494; to M.G.) and National Institutes of Health Grant R01-AI63419 (to C.M.W.).

² Current Address: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California.

³ Address correspondence and reprint requests to Dr. Craig M. Walsh, University of California, Irvine, 3215 McGaugh Hall, Irvine, CA 92697-3900. E-mail address: cwalsh{at}uci.edu

⁴ Abbreviations used in this paper: Treg, regulatory T cell; AICD, activation-induced cell death; ANA, anti-nuclear Ab; DAPK, death-associated protein-like kinase; DP, double positive; DRAK2, DAP-related apoptotic kinase-2; EAE, experimental autoimmune encephalomyelitis; HA, hemagglutinin; hGH-3' UTR, 3' untranslated region of human growth hormone; MOG, myelin oligodendrocyte glycoprotein; qPCR, quantitative real-time RT-PCR; SP, single positive; Tg, transgenic.

⁵ The online version of this article contains supplemental material.