Abstract Body: Mammalian heart regeneration is restricted to a brief postnatal period during which neonatal-specific mechanisms, including a tightly regulated immune response, enable effective tissue repair. T cells are increasingly recognized as important contributors to this process, yet studies to date have focused primarily on regulatory T cells, which represent only a minor fraction of the cardiac T cell compartment.

Using flow cytometry and single cell sequencing, we analyzed the T cell compartment of the neonatal mouse heart during the regenerative window (P2) and after regeneration capacity is lost (P8). We found that regenerative hearts specifically accumulate a distinct population of γδ T cells, whereas non-regenerative hearts exhibit a more conventional T cell composition dominated by αβ T cells. Further characterization identified cardiac γδ T cells as γδT17 cells, an innate-like T cell population that acts through the cytokine IL-17A and has not been previously implicated in cardiac injury. Genetic ablation of γδ T cells or disruption of IL-17 signaling limited the regenerative capacity of the neonatal heart and resulted in increased inflammation and fibrosis, as well as impaired cardiac function. Mechanistically, our data suggest that following neonatal cardiac injury, IL-17A produced by γδ T cells acts on macrophages and monocytes adjacent to the injury site to initiate a rapid inflammatory response that facilitates apoptotic cell clearance and prevents sustained inflammation.

Our study thus identifies a developmentally restricted γδ T cell–IL-17A axis that contributes to neonatal heart regeneration and advances our understanding of how neonatal-specific immune circuits shape tissue repair capacity.