Following organ transplantation, tissue parenchymal cells commonly express major histocompatibility complex (MHC) class II molecules as a result of local cytokine release, and thus acquire the capacity to present donor MHC alloantigens to alloreactive CD4+ T cells. The consequences of such a presentation are likely to be relevant in the induction of tolerance to the transplanted tissues, and this has been reported in animal models of transplantation and in humans. In this study, the consequences of antigen presentation by interferon-gamma (IFN-gamma)-treated human renal tubular epithelial cells (RTEC) to resting and activated CD4+ T cells were investigated. Allogeneic RTEC were unable to stimulate proliferation by peripheral blood CD45 RA+ or RO+ CD4+ T cells from three HLA-mismatched responders. The response to RTEC was partially reconstituted by the addition of murine L cell transfectants expressing human B7.1 (DAP.3-B7), suggesting that the failure of RTEC to stimulate a primary alloresponse was due, at least in part, to a lack of costimulation. T cell clones dependent on B7-mediated co-stimulation also did not respond to peptide presented by RTEC. Most importantly, this lack of reactivity was accompanied by the induction of nonresponsiveness. Incubation with allogeneic, DR-expressing RTEC induced allospecific hyporesponsiveness in both CD45RA+ and RO+ cells. Similarly, overnight incubation with antigen-pulsed RTEC induced nonresponsiveness in the B7-dependent T cell clones. These results suggest that MHC class II expression on RTEC may contribute to the induction of an allospecific nonresponsiveness following organ transplantation.