Regulation of A1 and Mcl-1 from costimulatory signals affects T cell survival (47.2)

Abstract

Abstract Costimulation is critical for T cell activation. In recent years, advances have been made in studies of costimulation as potential therapies in the treatment of diseases. However, the intracellular signals by which costimulation affects the function of T cells are not fully understood. A1 and Mcl-1, two bcl-2 family proteins are up regulated in effector T cells by ligation with an agonist antibody to the costimulatory molecule OX40 (CD134), which is essential for long-term T cell survival. To determine whether A1 and Mcl-1 are intracellular molecules of OX40, we examined A1 and Mcl-1 expression in primary T cells from wild-type and OX40-deficient mice, and found A1 and Mcl-1 were up-regulated after early T cell activation, but not be maintained in T cells from OX40-deficient mice. In addition, we used retrovirus-mediated transduction to introduce A1 or Mcl-1 into antigen (Ag)-responding T cells from OX40-deficent mice. We found that exogenous expression of A1 or Mcl-1 reversed the survival defect of OX40-deficient T cells both in vitro and in vivo. Moreover, sustained expression of A1 or Mcl-1 in CD8+ T cells from OX40-deficient mice reversed their defect in preventing tumor growth in a murine model. These results indicate that A1 and Mcl-1 are intracellular molecules of OX40, which regulate T cell survival. The data provide new insights into the mechanisms by which costimualtion regulates T cell survival.