Blocking PD1 prevents T-cell-promoted fibrosis in myocardial infarction.

Myocardial fibrosis is a common pathological feature that affects the outcome of various heart diseases, typically in the context of myocardial infarction (MI). The role of T cells in heart failure has been increasingly recognized, but whether programmed cell death protein 1 (PD1+) T cells modulate cardiac fibrosis during the post-MI pathological remodeling process remains unclear. Single-cell RNA sequencing and mass cytometry were conducted to determine the proportion of PD1+ T cells in both human ischemic diseases and a mouse MI model. Bulk RNA sequencing and cytokine arrays were used to investigate the function of PD1+ T cells. Cardiac function and histology were evaluated in non-human primates and rodents post-MI. We observed significant enrichment of PD1+ T cells in the heart after MI, which was positively associated with cardiac fibroblast activation and, hence, collagen secretion. Unlike in tumors, PD1+ T cells in the heart after MI demonstrated activated characteristics. PD1 knockout mice exhibited reduced cardiac fibrosis, resulting in increased cardiac performance following MI. Mechanistically, activated PD1+ T cells were found to drive fibrosis remodeling by modulating the CXCL9/CXCR3 axis through direct interaction with cardiac fibroblasts - an effect that occurred independently of the PD1/programmed death-ligand 1 (PD-L1) signaling pathway. Notably, anti-PD1 therapy in both mouse and non-human primate MI models effectively attenuated fibrosis and improved cardiac function without eliciting detectable adverse effects in non-cardiac organs. Our findings reveal a distinct PD-L1-independent pro-fibrotic mechanism mediated by PD1+ T cells during post-MI cardiac remodeling. Therapeutic inhibition of PD1+ T cells effectively suppressed fibrosis progression, highlighting its potential as an immunotherapeutic target for post-MI cardiac repair.