IL-17A-producing gdT cells promote muscle regeneration in a microbiota-dependent manner

Subsequent to acute injury, skeletal muscle undergoes a stereotypic regenerative process that re-establishes homeostasis. Various types of innate and adaptive immunocytes exert positive or negative influences at specific stages along the course of muscle regeneration. We describe an unanticipated role for gdT cells in promoting healthy tissue recovery after injection of cardiotoxin into murine hindlimb muscle. Within a few days of injury, IL-17A-producing gdT cells displaying primarily Vg6+ antigen receptors accumulated at the wound site. Punctual ablation experiments showed that these cells boosted early inflammatory events, notably recruitment of neutrophils; fostered the proliferation of muscle stem and progenitor cells; and thereby promoted tissue regeneration. Supplementation of mice harboring low numbers of IL-17A+ gdT cells with recombinant IL-17A largely reversed their inflammatory and reparative defects. Unexpectedly, the accumulation and influences of gdT cells in this experimental context were microbiota-dependent, unveiling an orthogonal perspective on the treatment of skeletal muscle pathologies such as catastrophic wounds, wasting, muscular dystrophies and myositides. Overall design: For sorted Vg6+ gdT cells, cells isolated from the colon and from injured skeletal muscle and these groups were analyzed relative to one another. For analysis of trizol lysed skeletal muscle, a time-course of wild-type control and gdT cell-depleted samples was collected. Analysis was between the gdT cell depleted sample relative to the respective wild-type controls at each time-point, additionally we examined how modules of genes changed over the time-course (and how this differed between genotypes). For analysis of the impact of IL-17 on muscle regeneration, we analysed samples from rIL-17 treated mice against PBS treated controls at a specific time-point (7 days after injury). For sorted muscle satellite cells, samples isolated from gdT cell depleted mice were compared against those isolated from wild-type controls mice. All cell types or treatment conditions are represented by 2-3 independent bioloigcal replicates