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Dual MHC Class I and Class II Restriction of a Single T Cell Receptor: Distinct Modes of Tolerance Induction by Two Classes of Autoantigens¹

Ivica Arsov and Stanislav Vukmanovi²

Michael Heidelberger Division of Immunology, Department of Pathology and Kaplan Cancer Center, New York University Medical Center, New York, NY 10016

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 TCRs with MHC molecules. It is currently thought that TCRs are preferentially restricted by either MHC class I or class II molecules. In this report, we present direct evidence 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 increase 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 II compared with that induced by H-Y/H-2D^b. We propose that 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.

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