Intracellular Galectin-3 Is Essential for OX40-Mediated Memory CD8⁺ T Cell Development

CD8⁺ T cells are critical mediators of adaptive immunity, and enhancing their function can promote robust responses against invading pathogens and neoplastic cells. In addition to TCR stimulation, the provision of costimulation through ligation of TNFR family members, such as OX40 (CD134), provides essential signals driving T cell differentiation, survival, and memory in part through enhanced IL-2/IL-2R signaling. Interestingly, TCR stimulation in the presence of IL-2 upregulates intracellular expression of the β-galactoside binding protein, Galectin-3 (Gal-3). Gal-3 has been shown to regulate Th1/Th2 polarization of CD4⁺ T cells; however, the extent to which Gal-3 regulates the OX40/IL-2 signaling axis and CD8⁺ T cell proliferation, effector function, and/or survival is unknown. In this study, we demonstrate that murine Gal-3-deficient CD8⁺ T cells exhibited no defects in early (36 h) activation or proliferation following TCR stimulation. In contrast, Gal-3^-/- CD8⁺ T cells exhibited decreased survival and a reduced capacity to develop into memory cells following stimulation with cognate Ag plus agonist anti-OX40 mAb or IL-2 in vivo. Decreased survival of Gal-3^-/- T cells was associated with increased apoptosis and occurred in a cell-intrinsic manner. Together, these data implicate intracellular Gal-3 as a critical mediator of OX40-mediated CD8⁺ T cell survival and memory formation following Ag exposure.