# Negative regulation of Lupus by the VISTA Pathway

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2021 · $342,271

## Abstract

VISTA (V-region Immunoglobulin-containing Suppressor of T cell Activation) is a member of the B7 negative
checkpoint regulator (NCR) family that controls normal immunity and prevents autoimmunity. Unlike other NCRs
(PD-1, BTLA, etc.), many of the unique immunologic activities of VISTA would predict an important role in
preventing SLE. VISTA has bi-directional functionality, acting as both a ligand and a receptor. As a ligand
expressed on myeloid cells, we have shown that it suppresses the earliest events in T cell activation through a
putative VISTA counter-receptor, V-set and immunoglobulin domain containing 8 (VSIG8). VISTA can also act
as a receptor on T cells and myeloid cells that regulates their biology. In addition, VISTA mediates the uptake of
apoptotic cells, a central mechanism in the pathogenesis of SLE. All of these functions bear heavily on the
central role of the VISTA-VSIG8 pathway in the development of SLE. In this application, we now provide genetic
proof that the VISTA pathway does indeed protect susceptible hosts from the development of fatal lupus.
Furthermore, we present evidence that VISTA may prevent end organ damage in SLE by regulating the critical
myeloid cell effector phase. Our identification of VSIG8 as the VISTA counter-receptor will allow us to elucidate
in full detail how this pathway controls the development of SLE. Furthermore, strategic approaches to target this
pathway for therapeutic gain will be tested. The unique engineered tools and genetic models we have created in
our lab will allow us to define the critical mechanisms by which the VISTA-VSIG8 pathway impacts on SLE.
Finally, these studies will facilitate the design of therapeutic strategies to intervene in human SLE, a disease
with a large unmet therapeutic need. Specific Aim 1. Identify the cellular and molecular mechanisms
responsible for the development of fatal SLE when the VISTA-VSIG8 pathway is disrupted. With the
lineage-restricted deficiency of VISTA in the T, myeloid and/or dendritic cell compartments, we will evaluate
how this loss results in the emergence of specific SLE pathologies and how VISTA deficiency on the sle1,3
background impacts on leukocyte immune function. Mice in which VSIG8 is conditionally-deleted will be used in
parallel to address the impact of VSIG8-deficiency in the development of SLE. Specific Aim 2. Define the
immune functions of VSIG8 as the VISTA counter-receptor. Studies show VSIG8 binds specifically to
VISTA and is involved with VISTA-mediated suppression. As little is known about the function of VSIG8 in the
immune system, a comprehensive, systematic approach is presented to demonstrate that VSIG8 is the receptor
for VISTA that mediates defined VISTA-specific functions in vitro and in vivo. Specific Aim 3. Targeting the
VISTA-VSIG8 pathway in SLE for therapeutic gain. Multiple strategies to target the VISTA-VSIG8 pathway to
achieve therapeutic success are presented. First is the use of VISTA-Ig that has demonstrated ...

## Key facts

- **NIH application ID:** 10168459
- **Project number:** 5R01AR070760-05
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** RANDOLPH J. NOELLE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $342,271
- **Award type:** 5
- **Project period:** 2017-02-10 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168459

## Citation

> US National Institutes of Health, RePORTER application 10168459, Negative regulation of Lupus by the VISTA Pathway (5R01AR070760-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10168459. Licensed CC0.

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