Injury- induced myosin- specific tissue- resident memory T cells drive immune checkpoint inhibitor myocarditis

• 成果类型: Article
• 署名作者: Kalinoski, Hannah; Daoud, Abdel; Rusinkevich, Vitali; Jurcova, Ivana; Talor, Monica V.; Welsh, Robin A.; Hughes, David; Zemanova, Katerina; Striz, Ilja; Hooper, Jody E.; Kautzner, Josef; Peichl, Petr; Melenovsky, Vojtech; Won, Taejoon; Cihakova, Daniela
• 署名单位: Johns Hopkins University; Johns Hopkins Bloomberg School of Public Health; Johns Hopkins University; Institute for Clinical & Experimental Medicine (IKEM); Johns Hopkins University; Institute for Clinical & Experimental Medicine (IKEM); Stanford University; University of Illinois System; University of Illinois Urbana-Champaign
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12309
• DOI: 10.1073/pnas.2323052121
• 发表日期: 2024-10-15
• 关键词: heart; interleukin-15; mice; localization; autoimmunity; activation; PROGRAMS; biology; trigger; il-15

摘要

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 T RM 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 T RM cells, which coexpress PD- 1 and CD69. To investigate whether the recruited MyHC T RM 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 T RM 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+ T RM cells that up- regulate PD- 1. Finally, we determined that human pericardial macrophages produce IL- 15, which supports and maintains pericardial T RM cells. Significance We determined that cardiac MyHC T RM cells are present in naive hearts and accumulate in the pericardial area in mice and humans after recovering from cardiac injury. T RM cells express high levels of PD-1, making them susceptible to activation by anti-PD-1 blocking antibodies. ICI-myocarditis is more prevalent after previous cardiac injury, demonstrating that T RM cells perpetuate the disease. Thus, our results provide unique insights into risk factors and the disease pathogenesis of ICI-myocarditis.