INVOLVEMENT OF DONOR T-CELL CYTOTOXIC EFFECTOR MECHANISMS IN PREVENTING ALLOGENEIC MARROW GRAFT-REJECTION

Donor CD8 cells play a pivotal role in preventing allogeneic marrow gr aft rejection, possibly by generating cytotoxic effecters needed to el iminate recipient T cells remaining after the pretransplant conditioni ng regimen or by producing cytokines needed to support the growth and differentiation of hematopoietic stem cells. In the present study, we assessed the role of donor T-cell cytotoxic effector function as a mec hanism for eliminating recipient CD8 cells that cause marrow graft rej ection in mice. The ability to prevent rejection was minimally affecte d by the presence of a defect in Fas ligand binding or by the absence of granzyme B but was severely affected by the absence of perforin. Do ubly mutant perforin-deficient, Fas ligand-defective CD8 cells were co mpletely unable to prevent rejection. Our results indicate first that recipient CD8 effecters responsible for causing marrow graft rejection are sensitive to cytotoxicity mediated by both perforin- and Fas-liga nd-dependent mechanisms, and second that donor T cells must have at le ast one functional cytotoxic mechanism to prevent allogeneic marrow gr aft rejection. (C) 1998 by The American Society of Hematology.