T lymphocyte bystander responses in male-biased myocarditis - Project Summary/Abstract Myocarditis, which is inflammation of the heart muscle mediated by immune cell infiltration and tissue damage, can lead to cardiac dysfunction or sudden death. The most common cause of myocarditis is viral infection, followed by other triggers including mRNA vaccination. Myocarditis, including after viral infection and vaccination, is more frequently seen in males, yet underlying mechanisms remain incompletely understood. A clearer understanding of male-biased myocarditis is essential for improving disease management and optimizing vaccine development. Previous work by us and others demonstrated that relative to healthy vaccinated controls, mRNA vaccine-associated myocarditis patients have elevations in circulating cytokines like IL-15, which activates T cells and innate-like bystander responses, coupled with increased peripheral activated cytotoxic T cells upregulating chemokine receptors, including CXCR3 and CCR5, implicated in heart tissue infiltration and site-specific bystander activation. In T cell bystander activation, memory T cells undergo nonspecific activation mainly via cytokines like IL-15 without TCR signaling or antigen recognition. Histopathological examination of patient heart biopsies confirmed predominant T cell infiltration. These immune responses have similarly been implicated in viral myocarditis, suggesting a potentially key role in male-biased heart inflammation. In preliminary studies, “dirty” mice with diverse prior microbial exposures and memory immune populations are shown to better model T cell bystander activation. Further, IL-15 administration in vivo, mimicking systemic triggers of pathology, induces male-biased bystander T cell responses and effects consistent with findings seen in myocarditis, which are reduced after androgen receptor blockade. Consistently, heart cytotoxic T cells were found to have elevated expression of the androgen receptor relative to various other tissues and immune subsets, with enhancing effects of androgens on heart bystander T cell activation signatures, which could explain the male bias and heart specificity. Based on this accumulating evidence, my hypothesis is that IL-15-induced bystander cytotoxic T cell responses mediate male-biased heart inflammation in an androgen-enhanced manner. To test this hypothesis, Aim 1 will define the role of IL-15-induced bystander T cells in male-biased heart inflammation using the developed dirty mouse in vivo system. Aim 2 will use androgen deprivation and supplementation to test effects on male-biased heart inflammation in vivo, including by multiplexed immunofluorescence spatial imaging. This study will advance our understanding of male-biased myocarditis and illuminate novel translational insights into sex immune differences and T cell bystander responses, both of which are widespread across numerous immune-mediated diseases. During this work, I will continue honing a unique skill set combining experimental techniques with powerful computational and bioinformatic approaches in an exceptional training and research environment toward a career advancing clinically relevant immunology as a physician-scientist.
