The DAP Kinases are serine/threonine kinases implicated in cell death. Mice deficient in a member of this family, Drak2, were produced by gene targeting and analyzed for lymphoid subsets and immune reactivity. Contrary to studies carried out using ectopic overexpression, no defect in activation induced cell death was noted in T lymphocytes or their progenitors. Instead, T cells from Drak2 -/- mice exhibit an autonomous hypersensitivity that renders them relatively independent of a requirement for CD28-mediated costimulation. Experiments are proposed to investigate the effect this co-stimulation independence has on induction and regulation of immunity. In addition, the signaling pathway regulated by DRAK2 will be investigated. Preliminary evidence indicates that it regulates the calcium-calcineurin activation pathway, and experiments will test this hypothesis by looking for biochemical interactions, and the dose-dependent regulation of NFAT activation. More generally, experiments are proposed to investigate the substrates of DRAK2 and the upstream mediators that affect DRAK2 activity. These experiments will elucidate a novel mechanism of immune regulation. The identification of a kinase that regulates the sensitivity of T cell activation constitutes in an important step in identifying therapeutics to regulate autoimmunity, immune responses to infectious agents, and tumor immunity. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI053091-01
Application #
6557442
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Mallia, Conrad M
Project Start
2002-12-15
Project End
2007-11-30
Budget Start
2002-12-15
Budget End
2003-11-30
Support Year
1
Fiscal Year
2003
Total Cost
$304,000
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
McGargill, Maureen A; Choy, Carmen; Wen, Ben G et al. (2008) Drak2 regulates the survival of activated T cells and is required for organ-specific autoimmune disease. J Immunol 181:7593-605
Wang, Shuhui; Welte, Thomas; McGargill, Maureen et al. (2008) Drak2 contributes to West Nile virus entry into the brain and lethal encephalitis. J Immunol 181:2084-91
Friedrich, Monica L; Wen, Ben G; Bain, Gretchen et al. (2005) DRAK2, a lymphoid-enriched DAP kinase, regulates the TCR activation threshold during thymocyte selection. Int Immunol 17:1379-90
McGargill, Maureen A; Wen, Ben G; Walsh, Craig M et al. (2004) A deficiency in Drak2 results in a T cell hypersensitivity and an unexpected resistance to autoimmunity. Immunity 21:781-91