Neonatal Regulatory T Cells Mediate Fibrosis and Contribute to Cardiac Repair

TL;DR

Neonatal hearts use special T cells to repair heart damage, and a protein called Rcn3 helps reduce scarring and improve recovery.

Contribution

The study identifies Rcn3 as a neonatal-specific protein in regulatory T cells that promotes heart repair and reduces fibrosis after injury.

Findings

Neonatal hearts have increased CD4+Foxp3+ T-reg cells with reparative programs after injury.

Rcn3 is upregulated in neonatal T-reg cells and is essential for heart recovery and anti-fibrotic effects.

Deleting Rcn3 in T cells impairs heart function recovery and increases fibrosis in mice.

Abstract

What are the main findings?
Neonatal hearts display a distinct post-infarction immune profile characterized by the accumulation of CD4+Foxp3+ T (T-reg) cells with reparative transcriptional programs.Reticulocalbin 3 (Rcn3) is selectively upregulated in neonatal T-reg cells and is required for functional recovery and suppression of fibrosis after myocardial infarction.

Neonatal hearts display a distinct post-infarction immune profile characterized by the accumulation of CD4+Foxp3+ T (T-reg) cells with reparative transcriptional programs.

Reticulocalbin 3 (Rcn3) is selectively upregulated in neonatal T-reg cells and is required for functional recovery and suppression of fibrosis after myocardial infarction.

What are the implications of the main findings?
Neonatal T-reg cells actively contribute to cardiac repair by modulating endoplasmic reticulum stress responses and paracrine anti-fibrotic signaling.Targeting T-cell-specific pathways such as Rcn3 may represent a novel immunomodulatory strategy to enhance myocardial repair in the adult heart.

Neonatal T-reg cells actively contribute to cardiac repair by modulating endoplasmic reticulum stress responses and paracrine anti-fibrotic signaling.

Targeting T-cell-specific pathways such as Rcn3 may represent a novel immunomodulatory strategy to enhance myocardial repair in the adult heart.

The neonatal heart possesses a unique capacity for reparative healing after myocardial injury, unlike the adult heart. While immune cells, particularly T cells, regulate post-infarction inflammation, their role in age-dependent cardiac repair remains unclear. This study aimed to characterize the temporal activation of T cell subsets and their contribution to immune homeostasis and myocardial repair. Myocardial infarction was induced in mice of different ages, and T cell subsets (CD4+ T cells, CD8+ T cells, and CD4+Foxp3+ T [T-reg] cells) were analyzed using flow cytometry and RNA sequencing. Neonatal hearts exhibited CD4+ T cells, CD8+ T cells, and T-reg cells that gradually increased until seven days post-injury. Transcriptome analysis identified Rcn3 as a neonatal-specific, injury-responsive gene in T-reg cells, with minimal induction in adult and aged hearts, promoting a reparative microenvironment and exerting anti-fibrotic effects via the PI3K/Akt pathway. Under endoplasmic reticulum stress, Rcn3 activated unfolded protein response genes, and Rcn3-conditioned media reduced fibrosis-associated gene expression in adult cardiac fibroblasts. In a conditional knockout mouse model (Lck-cre; Rcn3fl/fl), Rcn3 deletion in T cells led to impaired cardiac function recovery and increased fibrosis post-injury. These findings suggest that neonatal T-reg cells play a crucial role in cardiac repair, with Rcn3 as a potential therapeutic target for enhancing immune-mediated cardiac repair and limiting pathological remodeling in the adult heart.

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