Functional conditioning of CD8 T cells by thymoproteasome-dependent positive selection (P1408)

Abstract

Abstract Proteasomes play an important role in the production of peptides presented by MHC class I. The thymoproteasome, which contains β5t catalytic subunit, is expressed specifically in cortical thymic epithelial cells mediating the positive selection of DP thymocytes. In β5t-deficient mice, the cellularity of CD8SP thymocytes and peripheral CD8 T cells is significantly decreased and their TCR repertoire is altered as characterized by defective responses to alloantigens and viral infections. In the present study, we functionally characterized CD8 T cells generated in β5t-deficient mice. We found that CD8 T cells in the secondary lymphoid organs of β5t-deficient mice were enriched with CD44hiCD122hi memory-phenotype cells. This phenotypic alteration was marginal in the thymus but became apparent in the periphery of mice older than 1 week after birth, suggesting that CD8 T cells generated in the thymus of β5t-deficient mice are aberrantly maintained in the periphery. Surprisingly, the enrichment of memory-phenotype CD8 T cells was also seen in monoclonal β5t-/-Rag-/-OT-I mice. In addition, CD44loCD122lo cells obtained from β5t-/-Rag-/-OT-I mice showed enhanced proliferative responses to antigen stimulations. These results suggest that the thymoproteasome-dependent positive selection not only determines TCR recognition specificity but also preconditions T cell function.