Activated T lymphocytes are essential drivers of pathological remodeling in ischemic heart failure

Shyam S. Bansal, Mohamed Ameen Ismahil, Mehak Goel, Bindiya Patel, Tariq Hamid, Gregg Rokosh, Sumanth D. Prabhu

Research output: Contribution to journalArticlepeer-review

125 Scopus citations

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. When compared with sham-operated mice, mice with HF (8 weeks 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 expansion of splenic antigen-experienced effector and memory CD4+ T cells. Antibody-mediated CD4+ T-cell depletion in HF mice (starting 4 weeks after ligation) reduced cardiac infiltration of CD4+ T cells and prevented progressive left ventricular 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 left ventricular dysfunction, fibrosis, and hypertrophy in naive recipient mice. Conclusions - CD4+ T lymphocytes are globally expanded and activated in chronic ischemic HF, with Th2 (versus Th1) and Th17 (versus 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 on adoptive transfer.

Original languageEnglish
Article numbere003688
JournalCirculation: Heart Failure
Volume10
Issue number3
DOIs
StatePublished - Mar 1 2017

Keywords

  • T lymphocytes
  • adaptive immunity
  • adoptive transfer
  • heart failure
  • inflammation

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