Project Grant F30HL188450

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 NAIVE 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 (IFNG) 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.