Activated T Lymphocytes are Essential Drivers of Pathological Remodeling in Ischemic Heart Failure

Abstract

Background Inappropriately sustained inflammation is a hallmark of chronic ischemic heart failure (HF); however, the pathophysiological role of T-lymphocytes is unclear. Methods and Results Permanent coronary ligation was performed in adult C57BL/6 mice. As compared with sham-operated mice, mice with HF (8 w after ligation) exhibited the following features: 1) significant (p<0.05) expansion of circulating CD3+CD8+ cytotoxic and CD3+CD4+ helper (Th) T-lymphocytes, together with increased Th1, Th2, Th17, and regulatory T-cell (Treg) CD4+ subsets; 2) significant expansion of CD8+ and CD4+ T-cells in failing myocardium, with increased Th1, Th2, Th17, and Treg CD4+ subsets, marked reduction of the Th1/Th2 ratio, augmentation of the Th17/Treg ratio, and upregulation of Th2 cytokines; and 3) significantly increased Th1, Th2, Th17 cells, and Tregs, in the spleen and mediastinal lymph nodes, with increased expansion of splenic antigen-experienced effector and memory CD4+ T cells. Antibody-mediated CD4+ T-cell depletion in HF mice (starting 4 w after ligation) reduced cardiac infiltration of CD4+ T-cells and prevented progressive LV dilatation and hypertrophy whereas adoptive transfer of splenic CD4+ T-cells (and, to a lesser extent, cardiac CD3+ T-cells) from donor mice with HF induced long-term LV dysfunction, fibrosis, and hypertrophy in naïve recipient mice. Conclusions CD4+ T-lymphocytes are globally expanded and activated in chronic ischemic HF, with Th2 (vs Th1) and Th17 (vs Treg) predominance in failing hearts, and with expansion of memory T-cells in the spleen. Cardiac and splenic T-cells in HF are primed to induce cardiac injury and remodeling, and retain this memory upon adoptive transfer.

Genetic deletion of 12/15 lipoxygenase promotes effective resolution of inflammation following myocardial infarction

“…Splenic mononuclear cells heighten the immune response and promote LV remodeling and dysfunction in chronic ischemic heart failure [19, 20]. Previous studies have explained the recruitment of splenic monocytes and change in the architecture of spleen in response to MI [19, 32].…”

“…with slight modification [19, 20]. The viability was measured by using the trypan blue exclusion method.…”

“…The splenocytes for flow cytometry were isolated as described previously with slight modification [19, 20]. …”

Mineralocorticoid Receptor Deficiency in T Cells Attenuates Pressure Overload–Induced Cardiac Hypertrophy and Dysfunction Through Modulating T-Cell Activation

“…Recent data have indicated the involvement of memory T cells in pathologic cardiac remodeling. 26 Moreover, effector memory T cells (T EM , CD44 hi CD62L low ) are the main source of inflammatory cytokines, such as IFNγ (interferon-γ). 27,28 We further analyzed this T-cell subpopulation using flow cytometry ( Figure S1D).…”

Immunomodulation Is the Key to Cardiac Repair

“…Acute MI induces abrupt and massive cardiomyocyte death that triggers intense sterile inflammation to clear necrotic cells, followed by a reparative phase of inflammation resolution, neovascularization and scar formation. 2 Ischemic cardiomyopathy is accompanied by inappropriately sustained chronic inflammation, with expansion of innate 3, 4 and adaptive 5 immune cells and the elaboration of pro-inflammatory cytokines that promote adverse left ventricular (LV) remodeling. Attenuation of the cardiac inflammatory response may therefore represent a fruitful approach to enhance the efficacy of cell therapy in these diseases.…”