susceptible to DNTC-mediated regulation. Our data help explain the impaired peripheral clonal deletion observed in Fas mice (17) and suggest that in addition to regulatory cells, defects in the target cells that are being regulated may lead to the development of autoimmune diseases. Lpr DNTC-mediated regulation is similar to that previ- ously observed in Ld-specific DNTC T regulatory clones (11). Both cell types are able to kill syngeneic cells in vitro using a Fas-dependent mechanism. However, the DNTC clones generated from 2C transgenic mice only killed syn- geneic CD8 T cell targets that were activated by the same antigen (11), whereas primary activated lpr DNTC were able to kill syngeneic T cells that were activated by either the same or a different antigen in vitro. This finding is sim- ilar to that found using some subsets of primary activated CD4 CD25 T regulatory cells (20, 27), suggesting that cytotoxicity mediated by primary activated T regulatory cells is less specific than that mediated by transgenic DNTC clones. There are many possibilities that might explain the discrepancy between primary activated lpr DNTC and reg- ulatory DNTC clone-mediated killing in vitro. First, lpr DNTC used in these experiments were generated by stim- ulation with fully allogeneic splenocytes, whereas DNTC clones were generated from T cells that carry TCR reactive to only one specific epitope of the Ld antigen. Thus, there is a higher possibility for TCR-MHC cross-reaction with the H-2d–specific lpr DNTC compared with single class I locus (Ld)-specific DNTC clones. Second, nonspecific cy- totoxicity may result from high expression of FasL on lpr DNTC. Up-regulation of FasL on effector cells has been shown to induce nonspecific target cell death, termed by- stander killing (28). It is known that lpr DNTC constitu- tively express a higher level of FasL mRNA compared with non-lpr mice (15). Primary activation in vitro with alloge- neic cells and cytokines may induce overexpression of FasL on lpr DNTC resulting in bystander killing. In addition, in a recent study we have shown that the TCR on both DNTC and target T cells can influence non-lpr DNTC- mediated killing (unpublished data) and that in vitro anti- gen-specific killing can take place in many more conditions than was initially described using transgenic regulatory DNTC clones (11). Regardless of the in vitro discrepancy in antigen specificity, both regulatory DNTC clones (11) and lpr DNTC are able to suppress immune responses in an antigen-specific fashion in vivo. As seen in the DNTC clones, adoptive transfer of in vivo–activated lpr DNTC into wild-type syngeneic mice enhances donor-specific al- logeneic skin graft survival. Additional studies are needed in order to understand what mechanism is responsible for the discrepancy between the functions of in vitro– and in vivo–activated lpr DNTC. Although the ability of DNTC to inhibit allogeneic im- mune responses mediated by wild-type syngeneic CD4 and CD8 T cells was clearly demonstrated in this paper, it is not yet clear whether DNTC can also down-regulate syngeneic autoreactive T cells. The inability to identify the self-antigens that cause autoimmune disease in lpr mice makes it difficult to directly test the ability of lpr DNTC to suppress autoreactive T cells and prevent autoimmune dis- ease in these mice. More investigations into the mechanism and specificity of both regulatory cells and their targets will lead to a better understanding of the development of au- toimmune disease. 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