Antigen-specific suppression by induced CD4+CD25high regulatory T cells in kidney recipients

The biology and function of induced CD4(+)CD25(high) regulatory T (Treg) cells have not been clarified for their specificity to a foreign antigen. To test whether the regulatory functions of the induced CD4(+)CD25(high) Treg cells after transplantation require antigen-specific triggering, we analyzed the capacity of induced CD4(+)CD25(high) Treg cells to inhibit the proliferation of conventional CD4(+)CD25(-) T cells in response to T-cell receptor stimulation using donor cells or HLA-mismatched third-party cells in vitro. CD4(+)CD25(high) Treg cells did not proliferate in response to allogeneic stimulation and suppressed proliferation of the co-cultured autologous CD4(+)CD25(-) populations in a dose-dependent manner. The proliferation of CD4(+)CD25(-)T cells from the same donor in mixed lymphocyte reactions was significantly inhibited at a 1:8 ratio of conventional T cells:Treg cells: 14,404 +/- 673 cpm without CD4(+)CD25(high) Treg cells versus 10,781 +/- 539 cpm with CD4(+)CD25(high) Treg cells P = .01). At the same 1:8 ratio, the proliferation of CD4(+)CD25(-) cells derived from major histocompatibility complex-mismatched patients was not significantly inhibited: 14,404 +/- 673 cpm without CD4(+)CD25(high) Treg cells versus 12,471 +/- 709 cpm with CD4(+)CD25(high) Treg cells (P = .06). Antigen specificity of the induced CD4(+)CD25(high) Treg cells was demonstrated, after transplantation, supporting the use of antigen-specific Treg cells as a therapeutic strategy.