Structure and Functional Binding Epitope of V-domain Ig Suppressor of T-cell Activation (VISTA)

V-domain Ig Suppressor of T cell Activation (VISTA) is an immune checkpoint protein that inhibits the T-cell response against cancer. Similar to PD-1 and CTLA-4, antibodies that block VISTA signaling can release the brakes of the immune system and promote tumor clearance. VISTA has an Ig-like fold, but little is known about its structure and mechanism of action. Here, we report a 1.85 Angstrom crystal structure of the human VISTA extracellular domain and highlight structural features that make VISTA unique among B7 family members. Through fine-epitope mapping, we also identify solvent-exposed residues that underlie binding to a clinically relevant anti-VISTA antibody. This antibody-binding region is also shown to interact with V-set and Ig domain-containing 3 (VSIG3), the recently proposed functional binding partner of VISTA. The structure and functional epitope determined here will help guide future drug development efforts against this important checkpoint target.