T-regulatory cell protection of progenitor cells from CD4+ T-cell-mediated cytotoxicity is essential for endogenous mouse digit-tip regeneration

Regeneration of amputated digit tips in humans and mice relies on osteoclast-dependent bone erosion coupled with osteoblast-mediated bone replacement. Currently, little is known of the impact of lymphoid immune cells, i.e., T cells, B cells, and NK cells, on digit-tip regeneration. Using lymphoid-deficient mutant mice, we revealed lymphoid immunity as a net negative regulator of regeneration. CD8 + cells are thought to negatively regulate fracture repair; however, we showed that adoptive cell transfer (ACT) of CD8 + T cells into lymphoid-deficient hosts did not impact regeneration. In contrast, ACT of CD4 + T cells potently inhibited regeneration via osteoclast and osteoblast progenitor-cell cytotoxicity. CD4 + T-cell-mediated inhibition of regeneration was rescued by supplementation with T regulatory cells or recombinant RANKL, a mediator of osteoclast differentiation. ACT of IFN-γ-deficient CD4 + T cells abolished cytotoxic activity and rescued regeneration. Future strategies protecting endogenous progenitor cells could enhance human tissue repair and autologous stem-cell therapies.