Insight into the structure and function of empty class II major histocompatibility complexes

Abstract

Class II major histocompatibility complex (MHC) proteins bind peptides and present them at the cell surface for interaction with CD4+ T cells as part of the system by which the immune system surveys the body for signs of infection. Peptide binding is known to induce conformational changes in class II MHC proteins on the basis of a variety of hydrodynamic and spectroscopic approaches, but the changes have not been clearly localized within the overall class II MHC structure. Local structural changes were mapped for HLA-DR1, a common human class II MHC variant, using a series of monoclonal antibodies which recognize the beta subunit and are specific for the empty conformation. Additional structural information was obtained using side chain-specific chemical modification and identification of modified residues by in-gel tryptic digestion and mass spectrometric peptide mapping. Together, the chemical modification studies and the mapping results illuminate aspects of the structure of the empty forms and the nature of the peptide-induced conformational change. Empty class II MHC proteins have been observed on the surface of immature dendritic cells in both humans and mice. Immature DC also secrete a protease activity that is capable of generating antigenic peptides from whole antigen. The protease activity secreted by dendritic cells is characterized and the role of empty MHC proteins in dendritic cell antigen presentation is discussed.