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Background  Donor-specific blood transfusion (DST) prior to solid organ transplantation has been shown to induce long-term allograft survival in the absence of immunosuppressive therapy. Although the mechanisms underlying DST-induced allograft tolerance are not well defined, there is evidence to suggest DST induces one or more populations of antigen-specific regulatory cells that suppress allograft rejection. However, neither the identity nor the regulatory properties of these tolerogenic lymphocytes have been reported. Therefore, the objective of this study was to define the kinetics, phenotype and suppressive function of the regulatory cells induced by DST alone or in combination with liver allograft transplantation (LTx).    Methodology/Principal Findings  Tolerance to Dark Agouti (DA; RT1 a ) rat liver allografts was induced by injection (iv) of 1 ml of heparinized DA blood to naïve Lewis (LEW; RT1 l ) rats once per week for 4 weeks prior to LTx. We found that preoperative DST alone generates CD4 +  T-cells that when transferred into naïve LEW recipients are capable of suppressing DA liver allograft rejection and promoting long-term survival of the graft and recipient. However, these DST-generated T-cells did not express the regulatory T-cell (Treg) transcription factor Foxp3 nor did they suppress alloantigen (DA)-induced activation of LEW T-cells  in vitro  suggesting that these lymphocytes are not fully functional regulatory Tregs. We did observe that DST+LTx (but not DST alone) induced the time-dependent formation of CD4 + Foxp3 +  Tregs that potently suppressed alloantigen-induced activation of naïve LEW T-cells  in vitro  and liver allograft rejection  in vivo . Finally, we present data demonstrating that virtually all of the Foxp3-expressing Tregs reside within the CD4 + CD45RC −  population whereas in which approximately 50% of these Tregs express CD25.    Conclusions/Significance  We conclude that preoperative DST, in the absence of liver allograft transplantation, induces the formation of CD4 +  T-cells that are not themselves Tregs but give rise directly or indirectly to fully functional CD4 + CD45RC − Foxp3 + Tregs when transferred into MHC mismatched recipients prior to LTx. These Tregs possess potent suppressive activity and are capable of suppressing acute liver allograft rejection. Understanding the mechanisms by which preoperative DST induces the generation of tolerogenic Tregs in the presence of alloantigens may lead to the development of novel antigen-specific immunological therapies for the treatment of solid organ rejection.

Induction of Foxp3-Expressing Regulatory T-Cells by Donor Blood Transfusion Is Required for Tolerance to Rat Liver Allografts