T cells from H-Y TCR transgenic mouse: Evidence for a novel specificity to MHC class II and altered response to H-Y antigen

In the final stages of thymic development immature T cells undergo three distinct processes (positive selection, negative selection, and lineage commitment) that all depend on interactions of thymocyte T cell receptors (TCRs) with major histocompatibility (MHC) molecules. It is currently thought that TCRs are preferentially restricted by either MHC class I or class II molecules. It is demonstrated in this study that the TCR previously described as specific for the H-Y antigen presented by mouse MHC class I molecule H-2D b, crossreacts with self MHC class II molecule H-21Ab, if expressed in CD4+ cells. Strong upregulation of CD4 on CD4 +8+ thymocytes, as well as an increase in thymocyte numbers found in H-Y TCR trangenic mice deficient in MHC class II, suggest relatively discrete form of negative selection by MHC class II compared to that induced by H-Y/H-2Db. It is also proposed here that the inability to generate CD4+ T cells expressing H-Y TCR in different experimental settings may be due to tolerance to self MHC class II. These results, therefore, support an intriguing possibility that tolerance to self may influence and/or interfere with the outcome of the lineage commitment. It is also demonstrated in this study that H-Y/Db-specific CD8+ T cells from H-Y TCR transgenic mice were unable to lyse target cells expressing H-Y antigen. Stimulation of H-Y-specific effector CD8+ T cells with H-Y antigen, although insufficient to induce lytic granule release, was sufficient for H-Y-specific IFN-gamma production. Unexpectedly, this effector-phase IFN-gamma production was dependent on B7 engagement. Thus, costimulation can partially repair poor activation of transgenic CD8+ T cells by H-Y antigen due to low avidity/affinity of TCR-H-Y antigen/Db interaction and/or elevated threshold of CD8+ T cell activation.