Abstract Fri051: The Role of T Cell β2-Adrenergic Receptor Expression in Cardiac Remodeling in a Pressure-Overload Model of Heart Failure

Pathological cardiac remodeling is a hallmark of heart failure (HF) and influenced by immune mechanisms. In particular, T cells are known to contribute to fibrosis in HF due to multiple etiologies including pressure overload. Chronic sympathetic activation occurs in HF and modulates many aspects of cardiac function through adrenergic receptors (AR), including immune responses, however, the role of the sympathetic nervous system in regulating T cell responses is unknown. The β2AR subtype is highly expressed on CD4+ T cells, but the impact of β2AR signaling in CD4+ T cells on cardiac remodeling and fibrosis in HF remains to be fully elucidated. Thus, we hypothesized that CD4+ T cell β2AR expression plays a crucial role cardiac remodeling during HF. To study the effects of β2AR on T cells, a novel CD4+ T cell-specific β2AR knockout (tKO) mouse model was generated by crossing Adrb2 f/f mice with mice expressing Cre recombinase under the CD4 promoter. Mice underwent sham or transverse aortic constriction (TAC) surgery and cardiac function was assessed via serial echocardiography. Pathological remodeling was evaluated through histological, molecular and biochemical analysis. The influence of β2AR on inflammatory responses including differentiation, proliferation, cytokine production and migration were assessed in vitro using primary T cell populations and in vivo using standard immunological assays. Deletion of β2AR in CD4+ T cells led to a marked reduction in cardiac remodeling, fibrosis and reduced reductions in functional parameters, underscoring the critical role of CD4+ T cell β2AR signaling in driving the pathological changes associated with HF due to pressure-overload. Single-cell RNA sequencing identified changes in the immune cell populations infiltrating the heart in tKO animals after TAC compared to WT mice. Of the CD4+ T cell populations, Th1 cells had the highest β2AR expression and Th1 cells lacking β2AR had reduced secretion of key cytokines including interleukin (IL)-2 and interferon (IFN)-γ. β2ARKO Th1 cells had reduced expression of ICAM-1, resulting in impaired T cell/fibroblast interactions and reduced myofibroblast activation. These findings demonstrate that β2AR on CD4+ T cells plays a significant role in cardiac remodeling and fibrosis during HF through their interactions with cardiac fibroblasts and suggests that targeting β2AR in CD4+ T cells could offer a novel therapeutic approach to mitigating adverse cardiac remodeling in HF.