Regulation of skin and islet allograft survival in mice treated with costimulation blockade is mediated by different CD4+ cell subsets and different mechanisms

Background. Donor-specific transfusion (DST) and a brief course of anti- CD 154 monoclonal antibody (mAb) induces permanent islet and prolonged skin allograft survival in mice. Induction of skin allograft survival requires the presence of CD4(+) cells and deletion of alloreactive CD8(+) cells. The specific roles of CD4(+) and CD4(+)CD25(+) cells and the mechanism(s) by which they act are not fully understood. Methods. We used skin and islet allografts, a CD8(+) T cell receptor (TCR) transgenic model system, and in vivo depleting antibodies to analyze the role of CD4(+) cell subsets in regulating allograft survival in mice treated with DST and anti-CD 154 mAb. Results. Deletion of CD4(+) or CD25(+) cells during costimulation blockade induced rapid rejection of skin but only minimally shortened islet allograft survival. Deletion of CD4(+) or CD25(+) cells had no effect upon survival of healed-in islet allografts, and CD25(+) cell deletion had no effect upon healed-in skin allograft survival. In the TCR transgenic model, DST plus anti-CD154 mAb treatment deleted alloreactive CD8(+) T cells, and anti-CD4(+) mAb treatment prevented that deletion. In contrast, injection of anti-CD25 mAb did not prevent alloreactive CD8(+) T cell deletion. Conclusions. These data document that (1) both CD4(+)CD25(+) and CD4(+)CD25(+) cells are required for induction of skin allograft survival, (2) CD4(+)CD25(+) T cells are not required for alloreactive CD8(+) T cell deletion, and (3) CD4(+)CD25(+) regulatory cells are not critical for islet allograft tolerance. It appears that skin and islet transplantation tolerance are mediated by different CD4(+) cell subsets and different mechanisms.