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Circ Heart Fail. 2017 Mar;10(3):e003688. doi: 10.1161/CIRCHEARTFAILURE.116.003688.

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

Author information

1
From the Division of Cardiovascular Disease, Comprehensive Cardiovascular Center, University of Alabama at Birmingham (S.S.B., M.A.I., M.G., B.P., T.H., S.D.P.); and Medical Service, Birmingham Veterans Administration Medical Center, AL (S.S.B., S.D.P.).
2
From the Division of Cardiovascular Disease, Comprehensive Cardiovascular Center, University of Alabama at Birmingham (S.S.B., M.A.I., M.G., B.P., T.H., S.D.P.); and Medical Service, Birmingham Veterans Administration Medical Center, AL (S.S.B., S.D.P.). sprabhu@uab.edu.

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.

KEYWORDS:

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

[Indexed for MEDLINE]
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