Mechanism of  PD1 on cardiac inflammation resolution during heart failure development

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.

Grant Number: 5R01HL161085-04
NIH Institute/Center: NIH
Principal Investigator: YINGJIE CHEN