Abstract
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. ONE SENTENCE SUMMARY: Endogenous progenitor cells are vulnerable to CD4 (+) T-cell-mediated cytotoxicity during digit-tip regeneration and require T-regulatory-cell-mediated protection from autoimmune attack. HIGHLIGHTS: Digit-tip regeneration is enhanced with the loss of lymphoid immunity.Regeneration requires T regulatory cells (T-regs) for maintenance of osteoclastogenesis when other lymphoid cells are present.T-regs enhance regeneration in the absence of lymphoid immunity during the anabolic phase. Like thymic NK cells, CD4 (+) T cells and not CD8 (+) T cells are responsible for inhibition of regeneration. RANKL is essential to the rate-limiting catabolic phase of digit-tip regeneration. Both T-regs and recombinant RANKL can rescue CD4 (+) T-cell inhibition. Genetic knockout of key cytotoxicity genes (IFNγ, Prf1, and TNFα) in immune-competent mice enhances regeneration. CD4 (+) T-cell ACT induces both apoptosis and necroptosis. CD4 (+) T-cell cytotoxicity is dependent on IFNγ.