Tregs delivered post-myocardial infarction adopt an injury-specific phenotype promoting cardiac repair via macrophages in mice

Yasmin K. Alshoubaki, Bhavana Nayer, Yen-Zhen Lu, Ekaterina Salimova, Sin Nee Lau, Jean L. Tan, Daniela Amann-Zalcenstein, Peter F. Hickey, Gonzalo Monte-Nieto, Ajithkumar Vasanthakumar and Mikaël M. Martino ()
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Yasmin K. Alshoubaki: Monash University
Bhavana Nayer: Monash University
Yen-Zhen Lu: Monash University
Ekaterina Salimova: Monash University
Sin Nee Lau: Monash University
Jean L. Tan: Monash University
Daniela Amann-Zalcenstein: The Walter and Eliza Hall Institute of Medical Research
Peter F. Hickey: The Walter and Eliza Hall Institute of Medical Research
Gonzalo Monte-Nieto: Monash University
Ajithkumar Vasanthakumar: Olivia Newton-John Cancer Research Institute
Mikaël M. Martino: Monash University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Regulatory T cells (Tregs) are key immune regulators that have shown promise in enhancing cardiac repair post-MI, although the mechanisms remain elusive. Here, we show that rapidly increasing Treg number in the circulation post-MI via systemic administration of exogenous Tregs improves cardiac function in male mice, by limiting cardiomyocyte death and reducing fibrosis. Mechanistically, exogenous Tregs quickly home to the infarcted heart and adopt an injury-specific transcriptome that mediates repair by modulating monocytes/macrophages. Specially, Tregs lead to a reduction in pro-inflammatory Ly6CHi CCR2+ monocytes/macrophages accompanied by a rapid shift of macrophages towards a pro-repair phenotype. Additionally, exogenous Treg-derived factors, including nidogen-1 and IL-10, along with a decrease in cardiac CD8+ T cell number, mediate the reduction of the pro-inflammatory monocyte/macrophage subset in the heart. Supporting the pivotal role of IL-10, exogenous Tregs knocked out for IL-10 lose their pro-repair capabilities. Together, this study highlights the beneficial use of a Treg-based therapeutic approach for cardiac repair with important mechanistic insights that could facilitate the development of novel immunotherapies for MI.

Date: 2024
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DOI: 10.1038/s41467-024-50806-y

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