# VISTA is a negative checkpoint regulator of innate immunity

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2022 · $801,269

## Abstract

The overwhelming success of blocking negative checkpoint regulators (NCR; e.g. CTLA-4, PD-1) in cancer has
irrefutably validated NCRs as effective therapeutic targets in unleashing adaptive immunity in humans. We now
present compelling evidence that V-domain Ig suppressor of T cells (VISTA), in addition to its role in regulating
adaptive immunity, is a central negative regulator of innate immunity. Anti-VISTA mabs that trigger through
VISTA disrupt neutrophil and macrophage chemotaxis, alter the myeloid transcriptome and program myeloid
cells to an anti-inflammatory phenotype. Accordingly, anti-VISTA administration profoundly mitigates pathology
in autoimmune disease models mediated by the innate immune system. This proposal will comprehensively
address the impact of checkpoint regulation by VISTA on the genetics, epigenetics, biochemistry and
immunology of myeloid-mediated inflammation. SA#1. VISTA is expressed on neutrophils at very high densities
and we propose that VISTA is a central NCR of neutrophil activities. Data show that anti-VISTA triggering ablates
their chemotactic activities to inflammatory chemokines and arrests neutrophil-mediated inflammation in vivo. A
comprehensive analysis of VISTA negative regulation of neutrophil activation (chemotaxis, rolling, adhesion,
NETs, etc.) will be performed. Unparalleled mechanistic insights into the therapeutic impact of anti-VISTA in the
neutrophil-mediated K/BxN arthritis model will be provided by intravital microscopy in treated mice. SA#2. VISTA
acts as an NCR in monocytes and the mechanisms by which VISTA re-programs their biology will be
characterized. Within the macrophage lineage, we show that VISTA signaling directs macrophages to an anti-
inflammatory program. Defined by either macrophage tolerance or enhanced M1àM2 transition, VISTA elicits
a well-defined transcriptional and functional program that is anti-inflammatory. We propose that triggering
through VISTA can instruct myeloid reprogramming through the induction of a unique, VISTA-specific
transcriptional profile that ablates myeloid chemotaxis, mediator production and inflammation. SA#3. Anti-VISTA
ameliorates lupus by diminishing myeloid migration into the kidney and re-programming the inflammatory profile
of infiltrating myeloid cells. A correlation between the therapeutic impact of anti-VISTA and the treatment-induced
changes in myeloid heterogeneity and gene expression at the single cell level within the kidney will be
established. Furthermore, a comprehensive understanding of how anti-VISTA alters chemokine-dependent
positioning and the histological landscape of myeloid cells in the diseased kidney will be afforded by multiplex
imaging of myeloid subsets in anti-VISTA treated NZB/NZW F1 mice. Together, these two approaches will offer
unique insights into the negative regulation of innate immunity by VISTA in the pathogenesis of autoimmune
kidney disease. In summary, the experiments outlined herein will solidify the emerging ...

## Key facts

- **NIH application ID:** 10383777
- **Project number:** 5R01AI148430-03
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Rodwell Mabaera
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $801,269
- **Award type:** 5
- **Project period:** 2020-05-06 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10383777

## Citation

> US National Institutes of Health, RePORTER application 10383777, VISTA is a negative checkpoint regulator of innate immunity (5R01AI148430-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10383777. Licensed CC0.

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