Introduction: Acute myocardial infarction (MI) induces splenic remodeling and rapid mobilization of immune cells from the spleen to the injured myocardium. Activation of this “cardio-splenic” axis contributes to adverse cardiac remodeling and the development of chronic heart failure. B cells account for the majority of splenic immune cells, but their potential role within the cardio-splenic axis of heart failure remains incompletely explored. In this study, we provide evidence indicating that B cells play an essential role within the cardio-splenic axis via MHC II-mediated antigen presentation. Methods and Results: MI was induced in mice via permanent ligation of the left anterior descending coronary artery. Four weeks following MI or sham surgery, splenic B cells were isolated and transferred into healthy wild-type mice. Eight weeks after adoptive transfer, we assessed cardiac remodeling of recipient mice using echocardiography, gravimetric analysis, and histology. We found that the adoptive transfer of splenic B cells from post-MI mice was sufficient to induce adverse cardiac remodeling in recipient mice (Figure 1). Adoptively transferred splenic B cells were identified in the blood, spleen, and heart of recipient mice 8 weeks post-adoptive transfer. Single cell RNA sequencing (scRNAseq) of splenic B cells was then performed in mice following MI. Biological pathway analyses revealed dysregulation of signaling pathways related to antigen processing and presentation in post-MI mice, suggesting splenic B cells were modulating adverse cardiac remodeling via major histocompatibility complex class II (MHC II)-mediated antigen presentation (Figure 2). Therefore, we developed transgenic mice with B cell-specific MHC II deletion and repeated our adoptive transfer studies. The adoptive transfer of splenic B cells deficient in MHC II from post-MI mice did not induce adverse cardiac remodeling in naïve recipients (Figure 3). Transcriptomic analyses of peripheral blood B cells were also performed in post-MI human patients and healthy control patients, and showed similar dysregulation of antigen processing and presentation in B cells in both acute and chronic phases of MI. Conclusions: Following MI, splenic B cells recirculate along the cardio-splenic axis and contribute to adverse cardiac remodeling via MHC II-mediated antigen presentation. Our results thus point towards MHC II-mediated signaling in B cells as a novel and specific therapeutic target in heart failure.

Abstract 4140310: B cell-mediated antigen presentation promotes adverse cardiac remodeling in chronic heart failure