Background.

Donor-specific transfusion (DST) and a brief course of anti-CD154 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-CD154 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.