Tolerance to antigen-presenting cell-depleted islet allografts is CD4 T cell dependent

Pretreatment of pancreatic islets in 95% oxygen culture depletes graft-asso ciated APCs and leads to indefinite allograft acceptance in immunocompetent recipients. As such, the APC-depleted allograft represents a model of peri pheral alloantigen presentation in the absence of donor-derived costimulati on, Over time, a state of donor-specific tolerance develops in which recipi ents are resistant to donor APC-induced graft rejection, Thus, persistence of the graft is sufficient to induce tolerance independent of other immune interventions. Donor-specific tolerance could be adoptively transferred to immune-deficient SCID recipient mice transplanted with fresh immunogenic is let allografts, indicating that the original recipient was not simply "igno rant" of donor antigens, Interestingly, despite the fact that the original islet allograft presented only MHC class I alloantigens, CD8(+) T cells obt ained from tolerant animals readily collaborated with naive CD4(+) T cells to reject donor-type islet grafts. Conversely, tolerant CD4(+) T cells fail ed to collaborate effectively with naive CD8(+) T cells for the rejection o f donor-type grafts. In conclusion, the MHC class I+, II- islet allograft p aradoxically leads to a change in the donor-reactive CD4 T cell Subset and not in the CD8 subset, We hypothesize that the tolerant state is not due to direct class I alloantigen presentation to CD8 T cells but, rather, occurs via the indirect pathway of donor Ag presentation to CD4 T cells in the co ntext of host MHC class II molecules.