Immunomodulatory Effects of Regulatory T Cells Promote MSC Recruitment and Improve Titanium Osseointegration.

Abstract

T cells are lymphoid-derived cells that influence other immune cells in the inflammatory microenvironment by secreting cytokines and growth factors to facilitate inflammation resolution and new tissue formation. Our group has previously shown the importance of αβ T cells along with subsequent subsets of CD4+ and CD8+ T cells, both in vitro and in vivo, in reducing the polarization of pro-inflammatory macrophages, promoting the recruitment and proliferation of mesenchymal stem cells (MSCs), and enhancing new bone formation around modified titanium (Ti) implants. Regulatory T cells (Tregs) are a distinct subset of T cells that produce IL-10 and TGF-β, modulating immune responses and cytokine production in the local microenvironment. This study aimed to understand how Tregs influence the peri-implant microenvironment and new bone formation following implantation of modified Ti implants. We found that adoptive transfer of Tregs to wild-type mice significantly decreased pro-inflammatory macrophage polarization and cytokine production both in vivo and in vitro. Moreover, Treg transfer increased the proportion of anti-inflammatory macrophages and recruited MSCs, leading to markedly improved new bone formation at the peri-implant interface. In summary, our findings demonstrate that Tregs are crucial for resolving the pro-inflammatory response, speeding its resolution, and promoting bone regeneration in response to implanted Ti biomaterials. STATEMENT OF SIGNIFICANCE: This work uncovers a pivotal immunoregulatory role for regulatory T cells (Tregs) in shaping the peri-implant environment and enhancing osseointegration. By demonstrating that Treg adoptive transfer suppresses pro-inflammatory macrophage activity, promotes anti-inflammatory macrophage polarization, stimulates mesenchymal stem cell recruitment, and significantly improves new bone formation around titanium implants, this study identifies Tregs as essential drivers of inflammation resolution and tissue regeneration. These findings advance current understanding of immune-biomaterial interactions and highlight Tregs as a promising therapeutic target for improving the performance and clinical longevity of titanium-based implants.