Immunity
Volume 21, Issue 6, December 2004, Pages 781-791
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Article
A Deficiency in Drak2 Results in a T Cell Hypersensitivity and an Unexpected Resistance to Autoimmunity

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Abstract

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.

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1

These authors contributed equally to this work.

2

Present address: Department of Pharmacology, Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121.

3

Present address: Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697.