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Unraveling the role of V-domain immunoglobulin suppressor of T cell activation (VISTA) in atherosclerosis.

Award Number: F30HL188450
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/28/2027
PERIOD OF PERFORMANCE END DATE: 02/27/2028

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Unraveling the role of V-domain immunoglobulin suppressor of T cell activation (VISTA) in atherosclerosis. - PROJECT SUMMARY/ABSTRACT Atherosclerotic cardiovascular disease (CVD) is the leading cause of global mortality and morbidity and is defined as a lipid-driven chronic inflammatory disease of middle- and large-sized arteries. Risk of CVD events remains high despite success of lipid-lowering and anti-hypertensive treatments. The long-term goal of this proposal is to pursue immunotherapeutic solutions for CVD. The overall objective is to evaluate the role of immune checkpoint V-domain immunoglobulin suppressor of T-cell activation (VISTA) in atherogenesis. VISTA acts as both a ligand and a receptor on T cells to suppress naïve T cell activation, maintain T cell quiescence, and support regulatory T cell function. We found that VISTA is expressed on plaque T cell populations, and plaque VISTA expression is downregulated in individuals with symptomatic CVD. Further, we found that VISTA suppresses CD4+ T cell activation, proliferation, and interferon-gamma (IFNγ) production. This leads to the central hypothesis that CD4+ T cell VISTA expression is protective against plaque formation by inhibiting CD4+ T cell proliferation, activation, T helper 1 (Th1) differentiation, and migration. The central hypothesis will be tested by pursuing two specific aims: 1) Determine the role of T cell VISTA in atherosclerosis; and 2) Delineate the mechanisms of T cell suppression by VISTA. To study aim 1, we developed atherosclerotic mouse models with pan-cellular (VISTA-/-ApoE-/-), T cell (CD4creVISTAfl/flApoE-/-), or CD8-specific (CD8creVISTAfl/flApoE-/-) VISTA knockout. Plaque burden will be assessed pathologically, and immune profiling will be conducted via flow cytometry. The therapeutic potential of T cell VISTA will be explored by transferring VISTA-competent T cell subsets into CD4creVISTAfl/flApoE-/- mice during atherogenesis. In aim 2, VISTA will be knocked down within CD4+ and CD8+ T cells of mouse and human origin. These T cells will then be challenged using in vitro and in vivo proliferation, differentiation, and migration assays to determine how VISTA signaling effects T cell function. The proposed research is innovative as precise mechanisms of T cell suppression by VISTA have not yet been elucidated, and the role of VISTA in atherosclerosis remains unknown. The contribution is expected to be significant because it will provide foundational knowledge to lead the discovery of immunotherapies targeting VISTA in the CVD field and beyond. This work will directly promote the NIH mission of seeking knowledge to enhance health and lengthen life.


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 = $50,314 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	000	1	8/28/2026	NEW	$50,314
														Subtotal = $50,314

Grand Total All Awards = $50,314

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Unraveling the role of V-domain immunoglobulin suppressor of T cell activation (VISTA) in atherosclerosis.

Award Number: F30HL188450

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/28/2027

PERIOD OF PERFORMANCE END DATE: 02/27/2028

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