Abstract 17749: Immune Modulation by Regulatory T Cells Preserves Cardiac Function and Promotes Cardiomyocyte Proliferation After Myocardial Infarction
Inflammation after myocardial infarction (MI) eliminates dead cells and forms a reparative scar. Various animal models, in which the immune response is impaired, suggest that suppression of inflammation may promote cardiomyocyte proliferation. Here we assessed the hypothesis that the modulation of the immune system using regulatory T cells (T-regs) might be beneficial after MI.
We performed MI in the following immunodeficient mice (n = 8): Athymic Nude mice (T cell-deficient), SCID mice (T and B cell-deficient), SCID BEIGE mice (T, B and NK cell-deficient) and found that immunodeficient mice displayed preserved contractility relative to control mice (contractility index: 5.0±0.6, 7.0±1.1, 6.1±0.4, 6.9±0.7 in control, nude, SCID and SCID BEIGE mice respectively).
In accordance, T-reg depletion (using anti-CD25 antibodies or diphtheria toxin in DEREG mice, which have express the receptor selectively in T-regs), resulted in depressed cardiac function (EF: 55±6% in control vs 42±8% in depleted mice), increased infarct size (18±4% in control vs 44±7% in depleted mice), increased number of major events (such as aneurysms, cardiac ruptures and deaths). Histological analysis revealed increased inflammatory infiltration in T-reg depleted mice (CD45+ cells: 8±4% in control and 25±7% in depleted mice), as well as decreased number of fibroblasts (60±9% in control and 40±5% in T-reg-depleted mice). Consistently, EGFP+ T-regs, injected in the border region of the infarct (n=10) persisted in the heart for at least 1 week, reduced infarct size and preserved cardiac contractility (EF at 1 month: 35±6% in control and 55±11% in T-reg-injected mice). Of notice, close to the site of T-reg injection, we observed an increased number of EdU+ proliferating cardiomyocytes. Consistently, endogenous T-regs were found to be recruited very early after MI and this recruitment was paralleled by increased expression of Foxp3, TGF-β and IL-10 (markers of T-regs), as well as of IL-2, the main T-reg chemoattractant.
In conclusion, modulation of the immune system, and in particular local suppression of the immune system by T-reg activation at the site of MI, improves cardiac function, protects from major cardiac events and stimulates cardiomyocyte proliferation.
- © 2013 by American Heart Association, Inc.