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Although islet xenotransplantation is a promising therapy for type 1 diabetes, its clinical application has been hampered by cellular rejection and the requirement for high levels of immunosuppression. The aim of this study was to determine the role of Foxp3+ regulatory T (Treg) cells in costimulation blockade–induced dominant tolerance to porcine neonatal islet cell cluster (NICC) xenografts in mice.Porcine-NICC were transplanted under the renal capsule of BALB/c or C57BL/6 recipients and given a single dose of CTLA4-Fc at the time of transplant and 4doses of anti-CD154 mAb to day 6. Depletion of Foxp3+Treg cell was performed in DEpletion of REGulatory T cells mice at day 80 posttransplantation. Foxp3+Treg cell from spleens of treated BALB/c mice (tolerant Treg cell), and splenocytes were cotransferred into islet transplanted nonobese diabetic background with severe combined immunodeficiency mice to assess suppressive function.In treated mice, increased numbers of Foxp3+Treg cell were identified in the porcine-NICC xenografts, draining lymph node, and spleen. Porcine-NICC xenografts from treated mice expressed elevated levels of TGF-β, IL-10 and IFN-γ. Porcine-NICC xenograft tolerance was abrogated after depletion of Foxp3+Treg cell. Tolerant Treg cell produced high levels of IL-10 and had diverse T cell receptor Vβ repertoires with an oligoclonal expansion in CDR3 of T cell receptor Vβ14. These tolerant Treg cells had the capacity to transfer dominant tolerance and specifically exhibited more potent regulatory function to porcine-NICC xenografts that naive Treg cell.This study demonstrated that short-term costimulation blockade–induced dominant tolerance and that Foxp3+Treg cell played an essential role in its maintenance. Foxp3+Treg cells were activated and had more potent regulatory function in vivo than naive Treg cells.