PD1 blockade promotes IFN-γ production by progenitor exhausted PD1-expressing T cells in atherosclerotic plaques

Abstract Objective: Interferon-γ (IFN-γ) is a key cytokine regulating the development of atherosclerosis, but little known regarding phenotype and regulation T cells producing IFN-γ in plaques. Methods: To identify characterize IFN-γ-producing we utilized IFN-γ-YFP Nur77-GFP reporter mice crossed onto an atherosclerotic background (Apoe−/−IFN-γ YFP/YFP; Apoe−/−Nur77GFP/wt), adoptive transfer transgenic ApoB-reactive T-cells into containing humanized ApoB100 (HuBL mice), treatment with immune checkpoint inhibitors mice. Results: Aortic CD4 +and CD8 +T were complex set comprised predominantly “progenitor exhausted” PD1-intermediate (PD1 int) SLAMF6 +IL7R minor population “terminally PD1 hiTOX cells. However, both intand hiplaque Ki67 displayed elevated levels recent TCR signaling (Nur77-GFP +). ApoB-specific adoptively transferred to hypercholesterolemic HuBL showed sign early exhaustion, upregulating PD1, TOX, Tim3. Finally, blockade advanced atherosclerosis resulted increased production plaque-infiltrating Conclusion: plaque display markers classically associated exhausted cell still produce cytokines, proliferate, are responsive anti-PD1 treatment. Our study suggests that regulates plaques reveals potential mechanism by which therapy aggravates cardiovascular disease. Supported grants from Swedish Heart-Lung Foundation (#20200522, #20190449) sourced Daniel Engelbertsen.