International Immunology Advance Access originally published online on September 19, 2005
International Immunology 2005 17(11):1379-1390; doi:10.1093/intimm/dxh315
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DRAK2, a lymphoid-enriched DAP kinase, regulates the TCR activation threshold during thymocyte selection
1 Department of Molecular Biology and Biochemistry, Center for Immunology, University of California–Irvine, Irvine, CA 92697-3900, USA
2 Department of Biology, University of California, San Diego, La Jolla, CA 92093-0687, USA
3 University of California, San Diego Cancer Center
4 Present address: Genomics Institute of the Novartis Research Foundation, La Jolla, CA 92121, USA
5 Present address: Department of Pathology and Committee on Immunology, University of Chicago, Chicago, IL 60637, USA
Correspondence to: C. M. Walsh; E-mail: cwalsh{at}uci.edu
DAP kinases are a family of serine/threonine kinases known to regulate intrinsic apoptotic processes. DAP-related apoptotic kinase-2 (DRAK2) is highly expressed in lymphoid organs, with differential expression during thymocyte development. Low levels of transcript were observed in CD4/CD8 double-positive (DP) and double-negative populations, whereas single-positive thymocytes possessed elevated levels. Ex vivo stimulation of DP thymocytes with phorbol myristate acetate or antibodies that activate the TCR complex led to the accumulation of DRAK2 in a protein kinase C- and MAP Kinase-dependent fashion. Although DAP kinase family members are thought to potentiate apoptosis, ectopic expression of DRAK2 using retroviral transduction of primary T cells and NIH3T3 fibroblasts failed to decrease rates of survival, suggesting that DRAK2 expression is not sufficient to promote apoptosis. Rather, our results demonstrate that DRAK2 is a primary response gene activated by TCR stimulation in DP thymocytes. Further, we observed that DRAK2 controlled the threshold for calcium signaling in the thymus since positively selected Drak2-deficient thymocytes displayed a reduced requirement for TCR cross-linking. These findings are consistent with a role for DRAK2 in thymocyte selection and lymphoid maturation, and demonstrate that DRAK2 transduces non-apoptotic signals during thymocyte differentiation.
Keywords: DAP kinase, thymocytes, positive selection, T cells, signal transduction, central tolerance
Transmitting editor: Susan Swain
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