title: Loss of DRAK2 signaling enhances allogeneic transplant survival by limiting effector and memory T cell responses.
abstract: Here, we demonstrate that loss of DRAK2 signaling significantly promotes the acceptance of allogeneic engraftment in two separate transplant models without promoting generalized immunosuppression. Drak2-/- T cells failed to reject allogeneic tumors, and were defective in rejecting Balb/C allogeneic skin grafts on C57BL6/J recipients. A significant fraction of alloreactive Drak2-/- T cells underwent apoptosis following activation, whereas enforced expression of Bcl-xL in Drak2-/- T cells restored allograft rejection. Formation of allogeneic memory was also greatly hampered in T cells lacking the Drak2 gene. Adoptive transfer of memory T cells from Drak2-/- mice failed to promote the rejection of allogeneic tumors, and such cells led to significantly delayed rejection of skin allografts in the Balb/C->C57BL/6J model. Costimulatory blockade by in vivo administration of Cytotoxic T-Lymphocyte Antigen 4 fusion protein (CTLA4-Ig) synergized with the DRAK2 deficiency and led to long-term allogeneic skin graft acceptance. Overall, these results demonstrate that DRAK2 plays an important role in primary and memory T cell responsiveness to allografts. Because previous studies have demonstrated that a loss of DRAK2 does not negatively impact antiviral immunity, the studies here underscore the potential utility of pharmacological blockade of DRAK2 to achieve transplant maintenance without the imposition of generalized immunosuppression.
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA.
authors.forename: B M
authors.initials: BM
authors.lastname: Weist
authors.forename: J B
authors.initials: JB
authors.lastname: Hernandez
authors.forename: C M
authors.initials: CM
authors.lastname: Walsh
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D006085:Graft Survival; D007156:Immunologic Memory; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: C495197:Drak2 protein, mouse; D017346:Protein Serine-Threonine Kinases