Science 367, eaay0524 (2020)

VISTA is a negative regulatory molecule that, uniquely among checkpoint receptors, is expressed on naive T cells. In Science, Noelle and colleagues elaborate on the function of VISTA further and find that it has a cell-intrinsic role in maintaining naive T cell quiescence. VISTA’s absence results in the acquisition of T cell activation and memory transcriptional and epigenetic signatures, appears to operate specifically in the periphery and does not obviously influence thymocyte development. VISTA ligation results in increased sensitivity to T cell receptor activation-induced cell death and thereby helps maintain peripheral tolerance. However, under inflammatory conditions (for example, in the presence of lipopolysaccharide) VISTA expression is lost, and T cells can undergo activation and clonal expansion. VISTA therefore seems to be a checkpoint inhibitory receptor that enforces the quiescence of naive T cells under steady-state conditions.