| First Author | Johnston RJ | Year | 2019 |
| Journal | Nature | Volume | 574 |
| Issue | 7779 | Pages | 565-570 |
| PubMed ID | 31645726 | Mgi Jnum | J:286242 |
| Mgi Id | MGI:6402756 | Doi | 10.1038/s41586-019-1674-5 |
| Citation | Johnston RJ, et al. (2019) VISTA is an acidic pH-selective ligand for PSGL-1. Nature 574(7779):565-570 |
| abstractText | Co-inhibitory immune receptors can contribute to T cell dysfunction in patients with cancer1,2. Blocking antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) partially reverse this effect and are becoming standard of care in an increasing number of malignancies3. However, many of the other axes by which tumours become inhospitable to T cells are not fully understood. Here we report that V-domain immunoglobulin suppressor of T cell activation (VISTA) engages and suppresses T cells selectively at acidic pH such as that found in tumour microenvironments. Multiple histidine residues along the rim of the VISTA extracellular domain mediate binding to the adhesion and co-inhibitory receptor P-selectin glycoprotein ligand-1 (PSGL-1). Antibodies engineered to selectively bind and block this interaction in acidic environments were sufficient to reverse VISTA-mediated immune suppression in vivo. These findings identify a mechanism by which VISTA may engender resistance to anti-tumour immune responses, as well as an unexpectedly determinative role for pH in immune co-receptor engagement. |
