Dual MHC class I and class II restriction of a single T cell receptor: Distinct modes of tolerance induction by two classes of autoantigens

In the final stages of thymic development, immature T cells undergo three d istinct processes (positive selection, negative selection, and lineage comm itment) that all depend on interactions of thymocyte TCRs with MHC molecule s. It is currently thought that TCRs are preferentially restricted by eithe r MHC class I or class II molecules, In this report, we present direct evid ence that the TCR previously described as H-Y/H-2D(b) specific cross-reacts with H-2IA(b) if expressed in CD4(+) cells, We also demonstrate an increas e in thymocyte numbers in H-Y TCR-trangenic mice deficient in MHC class II, suggesting a relatively discrete form of negative selection by MHC class I I compared with that induced by H-Y/H-2Db. We propose that inability to gen erate CD4(+) T cells expressing H-Y TCR in different experimental settings may be due to tolerance to self-MHC class II. These results, therefore, sup port an intriguing possibility that tolerance to self may influence and/or interfere with the outcome of the lineage commitment.