The provision of T cell co-stimulation via members of the TNFR super-family, including OX40 (CD134) and 4-1BB (CD137), provides critical signals that promote T cell survival and differentiation. Recent studies have demonstrated that ligation of the OX40 receptor can augment T cell-mediated anti-tumor immunity in pre-clinical models and more importantly, several agonist OX40-specific agents are under clinical development for cancer immunotherapy. OX40 is of particular interest as a therapeutic target as it is not expressed on naïve T cells but rather, is transiently up-regulated following TCR stimulation. Although TCR engagement is necessary for inducing OX40 expression, whether additional downstream signals are needed to regulate OX40 remains unclear. In this study, we demonstrate that OX40 expression is regulated through a TCR and common gamma chain cytokine-dependent signaling cascade that requires JAK3-mediated activation of the downstream transcription factors STAT3 and STAT5. Furthermore, combined treatment with an agonist anti-OX40 mAb and IL-2R-directed cytokine therapy synergized to augment anti-tumor immunity by reviving the anti-tumor efficacy of anergic tumor-reactive CD8 T cells in vivo. Together, these data reveal the ability of TCR/common gamma chain cytokine signaling to regulate OX40 receptor expression and demonstrate a novel means of augmenting cancer immunotherapy by restoring the function of tumor-specific T cells.