Although immune tolerance is clearly important for the prevention of autoimmunity and the maintenance of lymphocyte homeostasis, suprisingly little is known about the intracellular signaling pathways that are involved. To this end, we have identified DRAK2, a serine/threonine kinase that is highly enriched in lymphoid tissues. As a member of the DAP family of kinases, DRAK2 induces apoptosis upon ectopic expression in certain cell lines. In mice with an engineered deficiency in DRAK2, a number of important defects in T lymphocyte development and activation are apparent. T cells derived from these mice are hyperproliferative to suboptimal stimulation through the T cell receptor, indicating an unexpected role in T cell quiescence for this kinase. In accord with this finding, DRAK2-/- mice have an increased proportion of activated T cells in peripheral lymphoid organs. Furthermore, DRAK2-deficient T cells proliferate in the absence of costimulatory signals normally required for T cell activation. We have found that whereas wildtype T cells require crosslinking of both the T cell receptor (TCR) and CD28 for a rapid and sustained calcium response, DRAK2-deficient T cells require only stimulation via the TCR. Paradoxically, clonal expansion following superantigen exposure is dramatically defective in DRAK2-deficient T cells. This defective responsiveness to superantigen is due to enhanced activation-induced cell death (AICD). We are curious about the mechanisms by which DRAK2 interferes with T cell activation and how its activity may modulate immune tolerance. We will determine if known T cell activation pathways are defective in DRAK2-/- mice. We will characterize the kinase biochemically to determine its mode of action. Finally, we will assess the consequences of its absence when AICD is blocked. These results are aimed at providing a more thorough understanding of negative regulation of T cell activation, and how such negative regulation contributes to immune tolerance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI063419-05S2
Application #
8093107
Study Section
Special Emphasis Panel (ZRG1-IMM-A (02))
Program Officer
Peyman, John A
Project Start
2010-06-28
Project End
2011-11-28
Budget Start
2010-06-28
Budget End
2011-11-28
Support Year
5
Fiscal Year
2010
Total Cost
$229,140
Indirect Cost
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Weist, B M; Hernandez, J B; Walsh, C M (2012) Loss of DRAK2 signaling enhances allogeneic transplant survival by limiting effector and memory T cell responses. Am J Transplant 12:2220-7
Yang, Kyung-Min; Kim, Wonjoo; Bae, Eunjin et al. (2012) DRAK2 participates in a negative feedback loop to control TGF-ýý/Smads signaling by binding to type I TGF-ýý receptor. Cell Rep 2:1286-99
Weinger, Jason G; Weist, Brian M; Plaisted, Warren C et al. (2012) MHC mismatch results in neural progenitor cell rejection following spinal cord transplantation in a model of viral-induced demyelination. Stem Cells 30:2584-95
Newton, Ryan H; Leverrier, Sabrina; Srikanth, Sonal et al. (2011) Protein kinase D orchestrates the activation of DRAK2 in response to TCR-induced Ca2+ influx and mitochondrial reactive oxygen generation. J Immunol 186:940-50
Lu, Jennifer V; Weist, Brian M; van Raam, Bram J et al. (2011) Complementary roles of Fas-associated death domain (FADD) and receptor interacting protein kinase-3 (RIPK3) in T-cell homeostasis and antiviral immunity. Proc Natl Acad Sci U S A 108:15312-7
Walsh, Craig M; Edinger, Aimee L (2010) The complex interplay between autophagy, apoptosis, and necrotic signals promotes T-cell homeostasis. Immunol Rev 236:95-109
Walsh, Craig M; Bell, Bryan D (2010) T cell intrinsic roles of autophagy in promoting adaptive immunity. Curr Opin Immunol 22:321-5
Hernandez, Jeniffer B; Newton, Ryan H; Walsh, Craig M (2010) Life and death in the thymus--cell death signaling during T cell development. Curr Opin Cell Biol 22:865-71
Bell, Bryan D; Walsh, Craig M (2009) Coordinate regulation of autophagy and apoptosis in T cells by death effectors: FADD or foundation. Autophagy 5:238-40
Gatzka, Martina; Newton, Ryan H; Walsh, Craig M (2009) Altered thymic selection and increased autoimmunity caused by ectopic expression of DRAK2 during T cell development. J Immunol 183:285-97

Showing the most recent 10 out of 17 publications