Th1 Effector T cells induce TGFβ mediated Cardiac Fibrosis in Pressure Overload induced Heart Failure by adhering to Alpha 4 Integrin and mediating Fibroblast Transformation

Cardiac fibrosis (CF) is a key factor contributing to the pathogenesis of the deadly syndrome of heart failure (HF). Recent emerging data demonstrate a role for T cells in pro‐fibrotic cardiac repair and healing post‐ischemia. However, very little is known about how T cells directly impact cardiac fibroblasts (CFB) to promote CF and cardiac dysfunction in non‐ischemic HF. Recently, we reported that T cells infiltrated the left ventricle (LV) of the heart in patients with end‐stage non‐ischemic HF, and also in the mouse model of non‐ischemic HF induced by thoracic aortic constriction (TAC). Interestingly, mice deficient in T cells (TCRα −/− mice) are protected from cardiac fibrosis (CF) and cardiac dysfunction. Thus, we hypothesize that T cells activated in such context orchestrate the activation and differentiation of fibroblasts to myofibroblasts. To test this hypothesis, we first co‐cultured adult CFB with T cells isolated from mice 4 weeks post TAC or Sham surgery. TAC but not Sham T cells firmly adhered to CFB and mediated myofibroblasts transformation as demonstrated by increased α‐SMA fluorescent expression. Co‐culture of various CD4 T cell subsets with CFB demonstrated that Th1 effector T cell subset, in contrast to naïve T cells, adhered directly to CFB through alpha 4 integrin and mediated myofibroblasts transformation in a TGFβ dependent manner. Moreover, adoptive transfer (AT) of effector Th1 cells, but not naïve T cells into TCRα −/− mice at 48 hours and 2 weeks post TAC surgery exclusively induced perivascular fibrosis that co‐localized with T cell and leukocyte infiltration and TGFβ expression. AT of Th1 cells also induced LV contractile and systolic dysfunction and a shift in the fetal gene expression of the myosin heavy chain α toβ which occurs in pathological cardiac remodeling. Taken together, these findings identify a novel role for Th1 cells in cardiac fibrosis and function and may provide innovative insights in the treatment of chronic non‐ischemic HF. Support or Funding Information NIH HL094706