FOXP3+ T Cells Recruited to Sites of Sterile Skeletal Muscle Injury Regulate the Fate of Satellite Cells and Guide Effective Tissue Regeneration

Abstract

Muscle injury induces a classical inflammatory response in which cells of the innate immune system rapidly invade the tissue. Macrophages are prominently involved in this response and required for proper healing, as they are known to be important for clearing cellular debris and supporting satellite cell differentiation. Here, we sought to assess the role of the adaptive immune system in muscle regeneration after acute damage. We show that T lymphocytes are transiently recruited into the muscle after damage and appear to exert a pro-myogenic effect on muscle repair. We observed a decrease in the cross-sectional area of regenerating myofibers after injury in Rag2-/- γ-chain-/- mice, as compared to WT controls, suggesting that T cell recruitment promotes muscle regeneration. Skeletal muscle infiltrating T lymphocytes were enriched in CD4+CD25+FOXP3+ cells. Direct exposure of muscle satellite cells to in vitro induced Treg cells effectively enhanced their expansion, and concurrently inhibited their myogenic differentiation. In vivo, the recruitment of Tregs to acutely injured muscle was limited to the time period of satellite expansion, with possibly important implications for situations in which inflammatory conditions persist, such as muscular dystrophies and inflammatory myopathies. We conclude that the adaptive immune system, in particular T regulatory cells, is critically involved in effective skeletal muscle regeneration. Thus, in addition to their well-established role as regulators of the immune/inflammatory response, T regulatory cells also regulate the activity of skeletal muscle precursor cells, and are instrumental for the proper regeneration of this tissue.

Cell death, clearance and immunity in the skeletal muscle

“…However, immune cells, including APCs, are in physiological conditions virtually absent and the tissue expression of MHC class I or class II molecules is limited (Figure 1). Moreover, the outcome of sterile inflammation in the skeletal muscle appears to be the recruitment of alternatively activated macrophages and of regulatory T cells that play non-redundant roles in muscle regeneration and possibly contribute to limit autoimmunity 7,8 (see below). Thus, muscle inflammation comprises signals that possibly contribute to initiate tissue regeneration and to terminate it in a timely manner once the tissue has healed and its homeostatic function is no longer required.…”

“…This action is mediated by the productive interaction with muscle stem cells. 7,8 In contrast, the accumulation of conventional CD4 + or CD8 + T lymphocytes reflects persistent inflammatory and immune-mediated injury, such as that taking place as a consequence of muscular dystrophy or inflammatory myopathies. 72,73 Figure 3 depicts some cellular players of muscle regeneration.…”

“…Lack of immunogenicity could depend on: (1) the lack of access of an intracellular moiety to APCs that must process and cross-present epitopes to autoreactive T cells; and/or (2) a still noncharacterized action in the maintenance of tolerance of Treg populations that are physiologically recruited during regeneration of the tissue. 7,8 Apoptotic HisRS-expressing myogenic precursors might represent a preferential substrate for phagocytic uptake and processing by APCs. In fact, several observations support the relevance of the link between apoptosis and autoimmunity that has been extensively studied in other contexts.…”

Inflammation et régénération musculaire

“…De même, in vitro, les lymphocytes sécrètent des cytokines susceptibles de favoriser directement la myogenèse [28]. Différentes études ont montré que les lymphocytes Treg favorisent la conversion des macrophages vers le phénotype anti-inflammatoire, qu'ils stimulent la prolifération des cellules satellites à la suite d'une blessure stérile et promeuvent la régénération musculaire (Figure 2) [29,30]. Cependant, d'autres études sont nécessaires afin de comprendre le rôle exact et les mécanismes d'action des différents types de lymphocytes dans la régénération musculaire stérile.…”

The Role of the Innate and Adaptive Immunity in Exercise Induced Muscle Damage and Repair

“…The initial inflammatory phase occurs in response to acute muscle damage; that is followed by the resolution phase whereby specific cell types are recruited into the damaged muscle; and finally the repair phase, which facilitates muscle regeneration and angiogenesis to reinstate tissue homeostasis ( Figure 1). A range of cell types can infiltrate injured skeletal muscle including innate leukocytes such as neutrophils, macrophages, NK cells, eosinophils and cells of the adaptive immune response including regulatory T cells and CD8 + T cells [8][9][10][11][12].…”