T_reg cells limit IFN-γ production to control macrophage accrual and phenotype during skeletal muscle regeneration.

Abstract

Skeletal muscle regeneration is a highly orchestrated process that depends on multiple immune-system cell types, notably macrophages (MFs) and Foxp3⁺CD4⁺ regulatory T (T_reg) cells. This study addressed how T_reg cells rein in MFs during regeneration of murine muscle after acute injury with cardiotoxin. We first delineated and characterized two subsets of MFs according to their expression of major histocompatibility complex class II (MHCII) molecules, i.e., their ability to present antigens. Then, we assessed the impact of T_reg cells on these MF subsets by punctually depleting Foxp3⁺ cells during the regenerative process. T_reg cells controlled both the accumulation and phenotype of the two types of MFs. Their absence after injury promoted IFN-γ production, primarily by NK and effector T cells, which ultimately resulted in MF dysregulation and increased inflammation and fibrosis, pointing to compromised muscle repair. Thus, we uncovered an IFN-γ-centered regulatory layer by which T_reg cells keep MFs in check and dampen inflammation during regeneration of skeletal muscle.