Following research that the CD96 receptor may play an inhibitory role on NK cells in mice, Lepletier, Lutzky, and Miles et al. evaluated the expression of CD96 in human immune cells. While CD96 was expressed on NK cells, it was more prominently expressed on T cells, particularly mucosal-associated invariant T (MAIT) cells, CD8+ T cells, and cells with central memory or effector memory phenotypes. CD96 expression correlated with antigen exposure and T cell activation; activated CD96hi T cells showed distinct effector functions. CD96 expression closely resembled that of CD226 and PD-1, and was distinct from TIGIT.
CD96 has recently been shown to be a potent immune checkpoint molecule in mice but a similar role in humans is unknown. In this study we provide a detailed map of CD96 expression across human lymphocyte lineages, the kinetics of CD96 regulation upon T cell activation and co-expression with other conventional and emerging immune checkpoint molecules. We show that CD96 is predominantly expressed by T cells and has a unique lymphocyte expression profile. CD96(high) T cells exhibited distinct effector functions upon activation. Of note, CD96 expression highly correlated with T cell markers in primary and metastatic human tumors and was elevated on antigen-experienced T cells and tumor infiltrating lymphocytes. Collectively, these data demonstrate that CD96 may be a promising immune checkpoint to enhance T cell function against human cancer and infectious disease. This article is protected by copyright. All rights reserved.