A MUTANT ANTIGEN-PRESENTING CELL DEFECTIVE IN ANTIGEN PRESENTATION EXPRESSES CLASS-II MHC MOLECULES WITH AN ALTERED CONFORMATION

Ag presentation by APC to class II MHC-restricted T cells involves a s equence of events: 1) intracellular processing of protein Ag into immu nogenic peptides, 2) specific binding of peptides to class II MHC mole cules, and then 3) transport of the MHC-peptide complexes to the plasm a membrane. The critical event in the activation of T cells by APC is the recognition of MHC-associated antigenic determinants by the TCR/CD 3 complex. In this report we describe the isolation and characterizati on of a mutant APC with a defect in an intracellular process that resu lts in its inability to form MHC-peptide complexes for recognition by T cells. The mutant APC cannot present many different protein Ag with both I-A and I-E molecules but is able to present processing-independe nt peptides. The functional defect in the mutant APC is not caused by either a decrease in expression or a structural mutation in class II M HC molecules. Further, there is no mutation in the invariant chain (li ) and it displays a normal kinetics of association and dissociation fr om the class II MHC molecules during biosynthesis. Although the mutati on is not in the genes encoding for the class II MHC molecules or li, the mutant APC expresses class II MHC molecules with distinct serologi cal epitopes suggestive of an altered conformation. Pulse-chase experi ments suggest that a conformational difference between I-A(d) molecule s of wild-type and mutant cells occurs after the class II molecules ex it from the endoplasmic reticulum but while they are still associated with li. The mutant cell produces few compact (SDS-resistant) class II heterodimers. This mutant APC provides a tool for studying the cell b iology of Ag processing and presentation.