Abstract 112: Endogenous-Antigen-Specific T Cell Receptor Activation of CD4+ T Cells in the Heart is Required for Maladaptive Cardiac Remodeling Due to Pressure Overload

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Cardiac pressure overload is associated with an adaptive immune response that drives maladaptive cardiac remodeling. CD4+ T cells are activated and expanded specifically in the heart-draining mediastinal lymph nodes (mLNs) and infiltrate the left ventricle (LV) in response to transverse aortic constriction (TAC). However, the specific mechanisms triggering T cell activation during the progression of TAC-induced HF remain unknown. We hypothesized that T cell receptor (TCR)-dependent activation of CD4+ T cells by endogenous antigens initiates and sustains maladaptive cardiac remodeling during the progression of TAC induced HF. We evaluated TCR mediated CD4+ T cell activation in the LV of Nur77 GFP mice, which transiently express GFP exclusively upon TCR stimulation. Strikingly, we found LV-infiltrated GFP + CD4+ T cells that increased in number as maladaptive remodeling and cardiac dysfunction progressed in response to TAC. Next generation sequencing of LV-sorted GFP + CD4+ T cells after 8 weeks of TAC revealed a limited repertoire of TCR clones relative to the periphery, demonstrating a restricted CD4+ T cell response to endogenous antigens. We further assessed the requirement for endogenous antigens by immunizing OT-II transgenic mice, which exclusively express a TCR specific for exogenous chicken ovalbumin (OVA), with OVA in the onset of TAC. While OVA induced CD4+ T cell activation and infiltration into the LV, this was not sufficient to induce cardiac dysfunction, demonstrating the importance of an endogenous antigen-specific response. Reactive isolevuglandins (IsoLGs) are formed during oxidative stress, and rapidly adduct to self-proteins forming endogenous neoantigens that elicit CD4+ T cell activation. We treated mice with the IsoLG scavenger 2-hydroxybenzylamine (2-HOBA) in the onset of TAC, which significantly reduced accumulation of IsoLG-protein adducts in dendritic cells, prevented CD4+ T cell activation in the mLNs, and prevented cardiac dysfunction. Thus, our results demonstrate that CD4+ T cell recognition of endogenous antigens in the LV, including IsoLG-protein adducts, via the TCR is required for maladaptive cardiac remodeling and cardiac dysfunction in pressure overload-induced HF.