CD279 mediates the homeostasis and survival of regulatory T cells by enhancing T cell and macrophage interactions

CD279 is a cell surface protein predominantly expressed on T cells. Its ligands CD273 and CD274 are expressed on antigen‐presenting cells and tumors. CD279 has been shown to act as an important immune check point by inhibiting CD8 T cell activation, and antibodies against CD279 enhance T cell‐mediated cytotoxic function. However, whether CD279 has other functions in CD4 T cell homeostasis or in mediating T cell interactions with antigen‐presenting cells remains unclear. In the present study, we show that antibody‐mediated inhibition of CD279 reduces T cell survival in bone marrow in vivo. Unexpectedly, CD279 blockade also compromised regulatory T cell and macrophage interactions by reducing their contact time. The observation that the CD273 antagonist had little effect suggests that CD274 (the second ligand of CD279) plays a more central role in contact between conventional T cells (Tcon) and macrophages. The results of the present study suggest that both CD279 ligands contribute to the interaction length between T cells and macrophages as a mechanism of maintaining Treg homeostasis. Furthermore, CD273 and CD274 are not redundant ligands because CD274 may have unique effects on Tcon in this complex immune axis. Therefore, ligand selection for check point blockade as a tool for cancer immunotherapy has important implications with respect to anti‐tumor T cell activation and the avoidance of side effects.