DOWN-MODULATION OF CD8 BETA-CHAIN IN RESPONSE TO AN ALTERED PEPTIDE LIGAND ENABLES DEVELOPING THYMOCYTES TO ESCAPE NEGATIVE SELECTION

Mice expressing a K-b-restricted transgenic T cell receptor (TCR) and a naturally occurring MHC class I variant molecule, K-bm8, were used t o study thymic selection, The transgenic TCR was specific for the majo r peptide determinant from ovalbumin (OVA(257-264)), while K-bm8 has a mutation that alters the position 2 binding pocket of the K-b molecul e, abolishing antigenic peptide presentation and positive selection of transgenic T cells, Peptide presentation was restored by identifying a position 2 analog peptide with K-bm8-binding capacity, In combinatio n with K-bm8, the E2 peptide variant was capable of deleting immature double-positive thymocytes in suspension culture. Similarly, addition of exogenous E2 peptide to fetal thymic organ culture resulted in effi cient deletion of double-positive thymocytes, However, there remained a population of CD8 single-positive T cells that exhibited impaired re sponsiveness to the antigenic peptide and lacked expression of the CD8 beta-chain, These results suggest a mechanism whereby developing thym ocytes bearing an alpha beta TCR can modify their expression of the CD 8 coreceptor to escape thymic deletion and achieve self-tolerance. (C) 1997 Academic Press.