CD96 functions as a co-stimulatory receptor to enhance CD8⁺ T cell activation and effector responses

CD96 is a member of the poliovirus receptor (PVR, CD155)-nectin family that includes T cell Ig and ITIM domain (TIGIT) and CD226. While CD96, TIGIT, and CD226 have important roles in regulating NK cell activity, and TIGIT and CD226 have also been shown to regulate T cell responses, it is unclear whether CD96 has inhibitory or stimulatory function in CD8⁺ T cells. Here, we demonstrate that CD96 has co-stimulatory function on CD8⁺ T cells. Crosslinking of CD96 on human or mouse CD8⁺ T cells induced activation, effector cytokine production, and proliferation. CD96 was found to transduce its activating signal through the MEK-ERK pathway. CD96-mediated signaling led to increased frequencies of NUR77- and T-bet-expressing CD8⁺ T cells and enhanced cytotoxic effector activity, indicating that CD96 can modulate effector T cell differentiation. Antibody blockade of CD96 or genetic ablation of CD96 expression on CD8⁺ T cells impaired expression of transcription factors and proinflammatory cytokines associated with CD8⁺ T cell activation in in vivo models. Taken together, CD96 has a co-stimulatory role in CD8⁺ T cell activation and effector function.