Introduction: The desired outcome of solid organ transplantation is a fully functioning organ that is tolerated by the transplant recipient’s immune system. Regulatory T cells (Treg) are imperative to the induction and maintenance of this allograft tolerance. Indeed, current tolerance induction strategies involve either induction or expansion of in vivo Tregs, or ex vivo preparations of recipient Treg for adoptive transfer. BM Treg have been identified as functionally superior to their circulating counterparts in both mice and humans but remain unstudied in solid organ transplantation. We have investigated the provenance, source and phenotype of Treg in tolerance and rejection transplantation models.
Methods: MHC mismatched donor and recipient mice were used for either orthotopic liver or heterotopic heart transplants. No immunosuppressant drugs were administered. Graft rejection was assessed by an experienced histopathologist. Allografts, bone marrow (BM), spleen, lymph nodes (LN) and blood were analysed by flow cytometry.
Results: Liver transplants experienced a transient rejection episode before tolerance was induced and maintained. Heart transplants succumbed to rejection by post-operative day (POD) 10-12. Liver tolerance, but not heart rejection, was associated with significantly increased numbers of Treg in the BM and their frequency within the BM T cell compartment. BM Treg expression of CD44 and TIGIT, molecules which are associated with maximal effector cell suppression, were increased with liver graft tolerance, but not heart rejection. No donor-derived Treg were detectable in either model past POD 7, confirming that all Treg functionality was recipient-derived.
Conclusion: We have identified recipient-derived effector BM Treg as major players in the tolerance of liver allografts. Further studies confirming the necessity of effector molecule expression and the ability of BM Treg to artificially induce tolerance in rejection models are currently being conducted.