Down-modulation of CD8 beta-chain in response to an altered peptide ligand enables developing thymocytes to escape negative selection.

Mice expressing a Kb-restricted transgenic T cell receptor (TCR) and a naturally occurring MHC class I variant molecule, Kbm8, were used to study thymic selection. The transgenic TCR was specific for the major peptide determinant from ovalbumin (OVA(257-264)), while Kbm8 has a mutation that alters the position 2 binding pocket of the Kb molecule, abolishing antigenic peptide presentation and positive selection of transgenic T cells. Peptide presentation was restored by identifying a position 2 analog peptide with Kbm8-binding capacity. In combination with Kbm8, 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 efficient deletion of double-positive thymocytes. However, there remained a population of CD8 single-positive T cells that exhibited impaired responsiveness to the antigenic peptide and lacked expression of the CD8 beta-chain. These results suggest a mechanism whereby developing thymocytes bearing an alphabetaTCR can modify their expression of the CD8 coreceptor to escape thymic deletion and achieve self-tolerance.