VISTA is a pH-selective checkpoint

T Cells The V-domain immunoglobulin suppressor of T cell activation (VISTA) is a negative checkpoint regulator that restrains T cell antitumor activity. VISTA modulates innate and adaptive immune responses using mechanisms unlike those of other immune checkpoint molecules. Johnston et al. report that under acidic pH conditions, such as those found within the tumor microenvironment, VISTA suppresses T cell activity. The researchers further show that VISTA deactivates immune responses because it is a ligand for the adhesion and coinhibitory receptor P-selectin glycoprotein ligand-1 (PSGL-1), which it engages through a histidine-rich interface. Disruption of VISTA–T cell interactions using acidic pH-selective antibodies could reverse T cell suppression. Modulation of VISTA may therefore provide a therapeutic means to enhance antitumor immunity. Nature 574 , 565 (2019).