Differential avidity and cyclosporine sensitivity of committed donor-specific graft-infiltrating cytotoxic T cells and their precursors. Relevance for clinical cardiac graft rejection.

We have used limiting dilution analysis to study the qualitative and quantitative differences between graft-infiltrating cytotoxic T cell populations propagated from endomyocardial biopsies of heart transplant patients who experienced one or more acute rejection episodes and patients who never showed signs of rejection. Limiting dilution cultures were stimulated with autologous or donor cells both in the absence or in presence of cyclosporine and of CD8 in the cytotoxic phase. Almost all antigen-primed, committed cytotoxic T cells (cCTL) present in the graft of patients with rejections were CsA resistant. In contrast, in most patients of the nonrejector group, a substantial part of the cCTL could be inhibited by CsA. The CTL precursors (pCTL) in both groups were predominantly CsA sensitive. Addition of CD8 mAb during the cytotoxicity phase of the limiting dilution analysis was used to differentiate between CTL populations with high avidity for donor antigens and populations with low avidity. The predominant subpopulation in the graft of rejectors was a CsA-resistant cCTL with high avidity, while in the graft of most nonrejectors, cCTL with low avidity dominated. In most rejectors, CD8 mAb had only a minor influence on the pCTL frequency estimates, and thus on T cells with high avidity. CsA-sensitive pCTL with high avidity might represent an intermediate stage between the naive pCTL and mature, functional, CsA-insensitive cCTL with high avidity for donor antigens.