Apoptotic cell administration enhances pancreatic islet engraftment by induction of regulatory T cells and tolerogenic dendritic cells.

Apoptotic cell transfer has been found to be able to facilitate engraftment of allograft. However, the underlying mechanisms remain to be fully understood. Here we demonstrate that intravenous administration of donor apoptotic splenocytes can promote pancreatic islet engraftment by inducing generation of tolerogenic dendritic cells (Tol-DCs) and expansion of CD4(+)Foxp3(+) regulatory T cells (Tregs). In vivo clearance of either dendritic cells (DCs) or Tregs prevented the induction of immune tolerance by apoptotic cell administration. Transient elimination of Tregs using anti-CD25, monoclonal antibody (mAb) abrogated the generation of Tol-DCs after administration of apoptotic splenocytes. Reciprocally, depletion of DCs within CD11c-DTR mice using diphtheria toxin (DT) prevented the generation of Tregs in the recipients with administration of apoptotic splenocytes. Induction of Tregs by Tol-DCs required direct cell contact between the two cell types, and programmed death 1 ligand (PD-L1) played important role in the Tregs expansion. Apoptotic cell administration failed to induce Tol-DCs in IL-10-deficient and Smad3-deficient mice, suggesting that IL-10 and transforming growth factor-β (TGF-β) are needed to maintain DCs in the tolerogenic state. Therefore, we demonstrate that Tol-DCs promote the expansion of Tregs via PD-L1 on their surface and reciprocally Tregs facilitate Tol-DCs to maintain transplantation tolerance induced by apoptotic cells via secreting IL-10 and TGF-β.