Back to Search Start Over

VISTA is an acidic pH-selective ligand for PSGL-1

Authors :
Johnston, Robert J.
Su, Linhui Julie
Pinckney, Jason
Critton, David
Boyer, Eric
Krishnakumar, Arathi
Corbett, Martin
Source :
Nature. October, 2019, Vol. 574 Issue 7779, p565, 6 p.
Publication Year :
2019

Abstract

Co-inhibitory immune receptors can contribute to T cell dysfunction in patients with cancer.sup.1,2. 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 malignancies.sup.3. 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. V-domain immunoglobulin suppressor of T cell activation (VISTA) selectively engages P-selectin glycoprotein ligand-1 (PSGL-1) and suppresses T cells at acidic pH similar to those in tumour microenvironments, thereby mediating resistance to anti-tumour immune responses.<br />Author(s): Robert J. Johnston [sup.1] , Linhui Julie Su [sup.2] , Jason Pinckney [sup.3] , David Critton [sup.4] , Eric Boyer [sup.1] , Arathi Krishnakumar [sup.5] , Martin Corbett [sup.6] [...]

Details

Language :
English
ISSN :
00280836
Volume :
574
Issue :
7779
Database :
Gale General OneFile
Journal :
Nature
Publication Type :
Academic Journal
Accession number :
edsgcl.639118085
Full Text :
https://doi.org/10.1038/s41586-019-1674-5