Cardiac myosin-specific (MyHC) T cells drive the disease pathogenesis of immune checkpoint inhibitor-associated myocarditis (ICI-myocarditis). To determine whether MyHC T cells are tissue-resident memory T (TRM) cells, we characterized cardiac TRM cells in naive mice and established that they have a distinct phenotypic and transcriptional profile that can be defined by their upregulation of CD69, PD-1, and CXCR6. We then investigated the effects of cardiac injury through a modified experimental autoimmune myocarditis mouse model and an ischemia-reperfusion injury mouse model and determined that cardiac inflammation induces the recruitment of autoreactive MyHC TRM cells, which coexpress PD-1 and CD69. To investigate whether the recruited MyHC TRM cells could increase susceptibility to ICI-myocarditis, we developed a two-hit ICI-myocarditis mouse model where cardiac injury was induced, mice were allowed to recover, and then were treated with anti-PD-1 antibodies. We determined that mice who recover from cardiac injury are more susceptible to ICI-myocarditis development. We found that murine and human TRM cells share a similar location in the heart and aggregate along the perimyocardium. We phenotyped cells obtained from pericardial fluid from patients diagnosed with dilated cardiomyopathy and ischemic cardiomyopathy and established that pericardial T cells are predominantly CD69+ TRM cells that up-regulate PD-1. Finally, we determined that human pericardial macrophages produce IL-15, which supports and maintains pericardial TRM cells.

• Klíčová slova
• ICI-myocarditis, PD-1, cardiac immunology, tissue-resident memory T cells,
• MeSH
• antigeny CD279 metabolismus   MeSH
• CD antigeny MeSH
• diferenciační antigeny T-lymfocytů metabolismus   imunologie   MeSH
• inhibitory kontrolních bodů * farmakologie   MeSH
• lektiny typu C metabolismus   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myokard imunologie   patologie   metabolismus   MeSH
• myokarditida * imunologie   patologie   metabolismus   MeSH
• myosiny metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• paměťové T-buňky * imunologie   metabolismus   MeSH
• srdeční myosiny imunologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD279 MeSH
• CD antigeny MeSH
• CD69 antigen MeSH Prohlížeč
• diferenciační antigeny T-lymfocytů MeSH
• inhibitory kontrolních bodů * MeSH
• lektiny typu C MeSH
• myosiny MeSH
• Pdcd1 protein, mouse MeSH Prohlížeč
• srdeční myosiny MeSH