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