Abstract 18758: Dysfunctional Regulatory T-lymphocytes are Pro-inflammatory and Anti-angiogenic in Heart Failure

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Abstract

Heart failure (HF) is a state of immune cell activation. Regulatory T-lymphocytes (Tregs) are potent immunomodulatory T-cells that suppress inflammatory responses; however, their role in HF is unknown. We tested the hypothesis that Tregs are dysfunctional in chronic ischemic HF, and promote chronic inflammation and pathological LV remodeling. We evaluated Treg distribution and function in male C57BL/6 and Foxp3-DTR Tg mice after coronary ligation and myocardial infarction (MI), or sham operation. CD4+Foxp3+ Tregs in ligated hearts were significantly increased (~3-4 fold) at 1 d, 1 w, and 8 w post-MI as compared with sham hearts, and were actively proliferating as assessed by BrdU incorporation. Circulating Tregs did not change early after MI (1 w), but were significantly increased thereafter (2, 4, 6, and 8 w), and were also increased in the spleen and mediastinal lymph nodes in chronic HF (8 w). In contrast to the early phase after MI, and as compared to corresponding sham-operated mice, Tregs in chronic HF exhibited diminished immunomodulatory capacity and significantly augmented expression of TNF and TNF receptor 1 (TNFR1) indicating a paradoxical pro-inflammatory phenotype. Treg ablation followed by subsequent reconstitution in chronic HF (4 w post-MI) was achieved by periodic diphtheria toxin (DT) administration in Foxp3-DTR mice (PBS control); mice were reassessed at 8 w post-MI. As compared with PBS control mice, Treg ablation in Foxp3-DTR HF mice significantly (p < 0.05): 1) improved LV dilatation, dysfunction, and hypertrophy, 2) enhanced circulating CD34+Flk1+ angiogenic cells, cardiac CCR5 and CCL5 expression, and tissue capillary density, 3) decreased border zone fibrosis, and 4) restored Treg immunosuppressive potential. These findings were recapitulated in C57BL/6 mice using anti-CD25 to induce Treg ablation. Furthermore, HF-activated Tregs were potently anti-angiogenic and significantly decreased invitro tube formation by mouse coronary endothelial cells in a juxtacrine and TNFR1-dependent manner. We conclude: dysfunctional Tregs in chronic ischemic HF exhibit pro-inflammatory and anti-angiogenic properties, in part dependent on TNF-TNFR1 signaling, that promote immune activation and pathological adverse remodeling.

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