Mechanism of  PD1 on cardiac inflammation resolution during heart failure development

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Cardiovascular inflammation promotes Heart failure (HF) development. However, mechanism of cardiac inflammation resolution during HF development is still poorly understood. Programmed cell death protein 1 (PD1) is a protein that keeps the body’s immune responses in check, both by inhibiting initial T cell induction and by maintaining T cell tolerance. PD1 blocking antibodies are used in cancer treatment, but the treatment also leads to cardiac toxicity in some patients. We found that PD1 KO or PD1 blocking antibodies dramatically exacerbated transverse aortic constriction (TAC)-induced cardiac inflammation, HF, and death, indicating PD1 exerts a more important role under stress conditions. To understand mechanisms of PD1 inhibition in cardiac inflammation, we studied cardiac immune cells and vascular endothelial cells from wild type and PD1 KO mice after sham or TAC by using single-cell CITE-seq together with barcoded antibodies for membrane protein labeling. Using single-cell CITE-seq, we also studied lung immune cells from HF mice and sham mice. Bioinformatics analyses have provided enormously information of these cells – showing dramatic alterations of cell clusters, enriched pathways of innate & adaptive immune responses, and changes of metabolic pathways in various immune cell subsets in HF mice, or in PD1 KO after TAC. gdT cells (a subset of T cells) can be divided into either IL-17 (gdT17) or IFNg producers. CITE-seq of lung immune cells showed that HF caused dramatic changes of various T cell and macrophage clusters, a dramatic increase of PD1 in Th17 and gdT17 cells, suggesting PD1 exerts an important role in suppressing Th17, and gdT17 cells as well as HF progression. CITE-seq in cardiac immune cells showed that infiltration of CD8+ T cells and gdT cells increased in PD1 KO mice after TAC, and these infiltrated cells are IFNg+ cells, indicating that CD8+ T cells, gdT cells, and IFNg may contribute to the exacerbated cardiac inflammation in PD1 KO mice. Based on these exciting findings, we hypothesize that TAC-induced cardiac and pulmonary inflammation resolution is regulated by PD1 through both conserved and unique pathways at least partially controlled by IFNg and IL17 produced by CD8+ T cells, gdT cells, and Th17, respectively. To enhance the innovative rigor of our investigation of the role of PD1 in cardiac inflammation and HF, we will also study CD8 cell specific PD1 KO mice. Aim-1. Test the hypothesis that IFNg and CD8+ T cells contribute to the exacerbated cardiac inflammation, cytokine storm, and HF in PD1 KO after TAC. In additon, we will determine whether PD1 KO in CD8+ T cells is sufficient to exacerbate TAC-induced cardiac inflammation and HF. Aim-2. Determine the roles and underlying mechanisms of IL17 and gdT cells in promoting TAC-induced cardiac inflammation and HF after PD1 inhibition. This application is highly responsive to the Notice of Special Interest NOT-ES-20-018 as the proposed studies will advance our understanding of the mechanisms of PD1 and T cells in cardiac and lung inflammation resolution, and the conserved & unique changes in cardiac and lung immune cell clusters during HF development and progression.