T-CELL SUPPRESSION IN TRANSPLANTATION TOLERANCE THROUGH LINKED RECOGNITION

Allogeneic tissues transplanted to mice treated with CD4- and CD8-spec ific Abs are often accepted indefinitely due to the induction of immun ologic tolerance. When transplantation tolerance was induced to grafts mismatched at multiple minor histocompatibility loci, Ag specificity was inferred because third party grafts, mismatched at the MHC, were r ejected normally. However, some ''third party'' grafts were either acc epted, or rejected more slowly, Tolerant mice possess CD4(+) cells, wh ich suppress rejection by T cells reacting to the same grafts. Therefo re, we hypothesized that tolerated third party grafts might share Ags with the original tolerizing graft, and that these Ags are a target fo r such suppression. To test this idea, we tolerized mice to a set of m inor Ags (B10 miners) and challenged them with third party grafts that carried those miners, as well as an additional strong transplantation Ag, the class I MHC molecule, H-2K(b). This class I molecule acts as a good target for rejection in both naive mice and in mice tolerized t o B10 miners. However, when this third party class I molecule is provi ded ''linked'' to those B10 miners on an F-1 graft, rejection was sign ificantly impaired. The data suggest that suppression within tolerant animals operates locally (perhaps on the same APC) via linked recognit ion. In addition, our preliminary findings suggest that suppression vi a linked recognition can also lead to tolerance to the third party Ag.