The Regulatory T Cell Response to Skeletal Muscle Injury and Its Decline With Age

Efficient skeletal muscle regeneration requires the accumulation of Foxp3+CD4+ regulatory T (Treg) cells. Muscle Tregs have a transcriptome and T cell receptor repertoire distinct from Tregs found in other tissues. The gene, Areg, was enriched in muscle Tregs and this molecule enhanced regeneration at the level of the satellite cell, a myogenic precursor. Il1rl1, which encodes for the interleukin(IL)-33 receptor, ST2, was also enriched in muscle Tregs. Our findings showed that muscle Tregs required expression of ST2 to both accumulate in injured muscle and potentiate repair. When we examined the producers of IL-33, we uncovered IL-33 was primarily produced by fibro/adipocyte progenitor cells, often in close association with neural structures, e.g. nerve tracts, bundles and muscle spindles, a muscle structure specialized for proprioception. Aging severely impairs skeletal muscle regeneration. Interestingly, although the Treg fraction in lymphoid organs increased with age, we found Treg accumulation in the injured muscle from aged mice was severely limited. Diminished Treg accumulation was due to impaired immigration from circulation, defective proliferation, and less efficient retention within muscle. Additionally, aging was accompanied by a decrease in IL-33-producing cells. When we administered exogenous IL-33, the aged muscle Treg population was restored to levels found in young mice, and regeneration was enhanced. In summary, these studies expand our understanding of this numerically small, but potent immune cell population. We uncover how aging impairs the Treg regenerative response, and in turn, highlight how IL-33 may potentially address age-related sacropenia and other muscle regeneration defects.Medical Science

Interleukin-33 in health and disease

Interleukin-33 (IL-33) — a member of the IL-1 family — was originally described as an inducer of type 2 immune responses, activating T helper 2 (TH2) cells and mast cells. Now, evidence is accumulating that IL-33 also potently stimulates group 2 innate lymphoid cells (ILC2s), regulatory T (Treg) cells, TH1 cells, CD8+ T cells and natural killer (NK) cells. This pleiotropic nature is reflected in the role of IL-33 in tissue and metabolic homeostasis, infection, inflammation, cancer and diseases of the central nervous system. In this Review, we highlight the molecular and cellular characteristics of IL-33, together with its major role in health and disease and the potential therapeutic implications of these findings in humans