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In DA rats grafted with PVG hearts a short course of cyclosporine induces a state of specific unresponsiveness. In animals with grafts surviving >75 days, the W3/25+(CD4+) subset loses its capacity to mediate rejection of PVG hut not third-party heart grafts when transferred into irradiated DA hosts. In this study we examined whether there was an associated change in the capacity of peripheral lymphoid T cell subsets from unresponsive animals to induce graft versus host (GVH) reactivity. First we demonstrated that there is synergy between naive CD4+and CD8+cells in the popliteal lymph node PLN assay, but that alone, only CD4+and not CD8+cells proliferate. Unfractionated and CD4+cells from unresponsive animals produced similar PLN enlargement in both donor-specific (DAxPVG)F1hosts and third-party (W/FxDA)F1, hosts. This enlargement was comparable to that produced cells from naive and specifically sensitized hosts. MBC OX8+cells from both unresponsive and naive hosts did not produce PLN enlargement unless large numbers were injected; small numbers of sensitized MRC OX8+cells produced specific PLN enlargement. CD4+cells from CsA-treated DA did not respond to DA anti-PVG idiotypein an in vivo assay adapted from the host versus graft (HVG) PLN assay. As the PLN assay does not test cells capacity to effect tissue damage, cells from CsA-treated DA rats were tested in a lethal GVHD assay. These cells had the same capacity to induce lethal GVH in irradiated (DAxPVG)F1and (DAxW/F)F1hosts. The normal response of cells from unresponsive animals in both proliferative and effector GVH assays slows that cells with the potential to respond to PVG alloantigen and mediate tissue damage are present in unresponsive animals but are prevented from mediating rejection, possibly due to the relatively weak. immune stimulus of an organ graft.