Positive selection of T lymphocytes expressing self-MHC-restricted T cell receptors is mediated by MHC molecules expressed on thymic stroma. Among the more controversial aspects of this process is the relative role of MHC molecules on epithelial versus bone marrow-derived stromal elements (BM- APC). For CD4+ T cells, the weight of evidence suggests that positive selection is driven solely by MHC class II molecules expressed on thymic epithelial cells. In contrast, recent experiments have been interpreted to show that CD8+ T cell development can be driven by MHC class I molecules expressed on BM-APCs as well as epithelial cells. To directly address this issue, we have examined the development of T cells expressing a transgenic MHC class I-restricted TCR in mice deficient in the rearrangement of endogenous TCR genes. Since the transgenic TCR is the only TCR expressed, this system is extremely sensitive and specific for detecting even inefficient events in T cell development. Our experiments demonstrate that MHC class I expression exclusively on BM-APC is incapable of driving positive selection of CD8+ T cells. This finding, together with earlier experiments for MHC class II, suggests a qualitatively unique function of thymic epithelial cells in mediating positive selection.
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