Hydrogen bond integrity between MHC class II molecules and bound peptide determines the intracellular fate of MHC class II molecules

MHC class II molecules associate with peptides through pocket interactions and the formation of hydrogen bonds. The current paradigm suggests that the interaction of side chains of the peptide with pockets in the class II mol ecule is responsible for the formation of stable class II-peptide complexes . However, recent evidence has shown that the formation of hydrogen bonds b etween genetically conserved residues of the class II molecule and the main chain of the peptide contributes profoundly to peptide stability. In this study, we have used I-A(k), a class II molecule known to form strong pocket interactions with bound peptides, to probe the general importance of hydro gen bond integrity in peptide acquisition. Our studies have revealed that a bolishing hydrogen bonds contributed by positions 81 or 82 in the beta -cha in of I-A(k) results in class II molecules that are internally degraded whe n trafficked through proteolytic endosomal compartments. The presence of hi gh-affinity peptides derived from either endogenous or exogenous sources pr otects the hydrogen bond-deficient variant from intracellular degradation. Together, these data indicate that disruption of the potential to form a co mplete hydrogen bond network between MHC class II molecules and bound pepti des greatly diminishes the ability of class II molecules to bind peptides. The subsequent failure to stably acquire peptides leads to protease sensiti vity of empty class II molecules, and thus to proteolytic degradation befor e export to the surface of APCs.