VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance

Abstract

Negative checkpoint regulators (NCRs) temper the T cell immune response to self-antigens and limit the development of autoimmunity. Unlike all other NCRs that are expressed on activated T lymphocytes, V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) is expressed on naïve T cells. We report an unexpected heterogeneity within the naïve T cell compartment in mice, where loss of VISTA disrupted the major quiescent naïve T cell subset and enhanced self-reactivity. Agonistic VISTA engagement increased T cell tolerance by promoting antigen-induced peripheral T cell deletion. Although a critical player in naïve T cell homeostasis, the ability of VISTA to restrain naïve T cell responses was lost under inflammatory conditions. VISTA is therefore a distinctive NCR of naïve T cells that is critical for steady-state maintenance of quiescence and peripheral tolerance.

VISTA: Coming of age as a multi-lineage immune checkpoint

“…While VISTA is not expressed on B cells, it is significantly expressed on plasma cells ( Lines and ElTanbouly, unpublished observations). Of note, we and others have detected reduced VISTA expression under inflammatory conditions .…”

“…The role of VISTA as an inhibitory receptor on T cells was first confirmed by Chen and colleagues, who showed that targeting VISTA with a novel class of agonistic antibodies can completely prevent acute graft‐ versus ‐host disease (GVHD) induction . We have expanded upon these data and showed that selective targeting of donor alloreactive T cells is sufficient for the anti‐VISTA prophylactic effect in GVHD . Of relevance, a recent study found that VISTA was expressed by myeloid cells of the corneal stroma and that genetic deficiency or blockade of VISTA significantly reduced corneal allograft survival .…”

“…Our analysis of the Encyclopaedia of DNA Elements (ENCODE) database for putative transcription factor (TF) binding to the VISTA promoters revealed multiple candidates. These include Fos, transcription factor JunD and nuclear factor kappa B (NF‐κB) . As these TFs are up‐regulated under inflammatory conditions, we predict that they are potential repressors of VISTA expression.…”

“…On lymphocytes, VISTA is most highly expressed on naive CD4 + T cells as well as forkhead box protein 3 (FoxP3) + T regulatory cells (T regs ). It exhibits lower expression levels on CD8 + T cells, natural killer (NK) cell subsets and thymocytes . While VISTA is not expressed on B cells, it is significantly expressed on plasma cells ( Lines and ElTanbouly, unpublished observations).…”

Single cell transcriptional and chromatin accessibility profiling redefine cellular heterogeneity in the adult human kidney

“…An advantage of snATAC-seq is the ability to measure covariance between accessible chromatin sites to predict cis-regulatory interactions 14 . This approach can link putative regulatory regions with their target genes and has been applied to human pancreatic islets 73 , acute leukemia 74 , and multiple mouse tissues, including: hippocampus 75 , mammary gland 76 , T-cells 77 , and kidney among others 8,9 . In particular, genome wide association study (GWAS) risk loci can be linked to their target genes, which would complement the progress made using chromosome conformation capture (Hi-C) 33 .…”