Inflammation is a hallmark of chronic heart failure (HF). Previously, we showed diffuse helper T-cell (Th) expansion with increased cardiac infiltration of Th2 and Th17 cells, and regulatory T-cells (Tregs), in chronic ischemic HF. However, the function of CD4+ T-cells in HF remains poorly defined. We hypothesized that T-cells are activated and critically regulate the progression of LV remodeling in ischemic HF. We characterized activation status of CD3+CD4+ T-cells - Th1 (IFNγ+), Th2 (IL-4+), Th-17 (IL-17+) and Tregs (Foxp3+) - by measuring high-affinity lymphocyte function associated antigen-1 (LFA-1) expression, and also identified antigen-experienced CD4+ effector (CD44hiCD25+) and memory (CD44hiCD25–) T-cells in male C57Bl/6 mice with HF induced by coronary ligation, and in sham-operated controls (assessed 8 w after surgery). Flow cytometry of cardiac mononuclear cells revealed that nearly all CD4+ T-cells (95-100%) in failing hearts expressed high-affinity LFA-1 integrin, with significantly (p < 0.05) augmented levels over sham hearts (Th1 170±34%; Th2 179±18%; Th17 158±55%; and Tregs 183±85%), suggesting an important role for LFA in T-cell recruitment to failing hearts. The HF spleen mirrored these changes with significantly increased splenic levels of high affinity LFA-1+ Th1 (147±19%), Th2 (142±24%), Th17 (193±77%), and Tregs (174±59%) as compared to spleens from sham mice. Moreover, antigen-experienced effector and memory CD4+ T-cells were also significantly increased in HF splenocytes, consistent with our prior studies demonstrating the induction of LV dysfunction in naïve mice after adoptive transfer of HF-activated splenic CD4+ T-cells. HF mice also exhibited increased abundance of circulating high-affinity LFA-1+ Th2 cells, Th17 cells and Tregs (but not Th1 cells) as compared to sham mice. Importantly, antibody mediated CD4+ T-cell depletion in HF mice resulted in improvements in cardiac function and attenuation of LV remodeling as compared with isotype IgG injected HF control mice. We conclude that CD4+ T-cells are activated and primed to induce pathological cardiac remodeling in chronic ischemic HF, and that CD4+ T-cell depletion may represent a feasible approach to therapeutic immunomodulation in this disease.Author Disclosures: S.S. Bansal: None. M. Ismahil: None. M. Goel: None. B. Patel: None. H. Zhong: None. T. Hamid: None. S.D. Prabhu: None.