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VISTA is a negative checkpoint regulator of innate immunity

Award Number: R01AI148430
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/06/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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VISTA is a negative checkpoint regulator of innate immunity - 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 role of VISTA as a critical NCR in innate immunity.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$837 )
2026	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	5	1/28/2026	NON-COMPETING CONTINUATION	-$837
														Subtotal = -$837

Issue Date FY: 2024 ( Subtotal = $792,298 )
2024	2024	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	5	5/3/2024	NON-COMPETING CONTINUATION	$792,298
														Subtotal = $792,298

Issue Date FY: 2023 ( Subtotal = $796,349 )
2023	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	4	3/28/2023	NON-COMPETING CONTINUATION	$796,349
														Subtotal = $796,349

Issue Date FY: 2022 ( Subtotal = $801,269 )
2022	2022	TRUSTEES OF DARTMOUTH COLLEGE	6001 PARKHURST HALL STE 207	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	3	4/4/2022	NON-COMPETING CONTINUATION	$801,269
														Subtotal = $801,269

Issue Date FY: 2021 ( Subtotal = $804,549 )
2021	2021	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	001	2	4/5/2021	NON-COMPETING CONTINUATION	$804,549
2021	2020	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	1	12/31/2020	NEW	$0
														Subtotal = $804,549

Issue Date FY: 2020 ( Subtotal = $820,549 )
2020	2020	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	1	5/5/2020	NEW	$820,549
														Subtotal = $820,549

Grand Total All Awards = $4,014,177

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VISTA is a negative checkpoint regulator of innate immunity

Award Number: R01AI148430

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/06/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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