Increased CD4+CD25+Foxp3+ regulatory T cells in tolerance induced by portal venous injection.

Abstract

A portal vein injection (PVI) of allogeneic donor antigen is known to prolong the survival of a subsequently transplanted allograft; however, the underlying mechanism remains to be clarified. Irradiated C57BL/6 (B6) splenocytes were injected into BALB/c mice via the portal vein. Seven days after injection, the proportions of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells were determined in the blood, liver, and spleen. CD4(+) and CD8(+) T cells were isolated from BALB/c mice that received PVI of B6 splenocytes (PVI mice), adoptively transferred into recipient BALB/c mice 1 day before B6 or third-party C3H heart transplantation, and graft survival was compared. B6 or C3H heart allografts were implanted into anti-CD25 monoclonal antibody (mAb)-treated PVI and untreated PVI mice, and graft survivals were compared. The percentages of CD4(+)CD25(+)Foxp3(+) Treg, cytokine profiles, and ratios of apoptosis were determined in anti-CD25 mAb-treated PVI and untreated PVI mice. PVI of allogeneic cells induced antigen-specific tolerance and increased the percentage of CD4(+)CD25(+)Foxp3(+) Treg. Adoptive transfer of CD4(+) T cells, but not CD8(+) T cells, from PVI mice prolonged B6 heart allograft survival. Depletion of CD4(+)CD25(+) T cells prevented the induction of tolerance and decreased the percentage of CD4(+)CD25(+)Foxp3(+) Treg in the CD3(+) T-cell pool, and thus was associated with decreased production of interleukin (IL)-4 and apoptosis of T cells. Increased CD4(+)CD25(+)Foxp3(+) Treg play an important role in portal vein tolerance induction, at least partly via increasing the production of IL-4 and decreasing apoptosis of T cells.