A STUDY OF THE MECHANISM BEHIND THE HLA-DO ACCESORY MOLECULE AND ITS GREATER ROLE IN CLASS II ANTIGEN PRESENTATION

[摘要] Antigen presentation is the first step in generating an adaptive immune response to a foreign pathogen. The antigen processing system digests antigens into small peptide fragments, which are bound to major histocompatibility complex (MHC) molecules to be presented to T cells. Our study focuses on the MHC class II (MHC II) system, which is responsible for presenting antigens to CD4+ T cells. Here, we examine the function of the MHC II accessory molecule HLA-DO (DO), and its interaction with another accessory molecule HLA-DM (DM), to regulate the nature of the peptides presented to CD4+ T cells. Although the genes encoding the DO proteins are evolutionary conserved in the MHC of mammals, their functions have not been well studied. To directly examine DO function, we designed a recombinant soluble DO heterodimer and tested its effect on peptide binding in vitro. The leading model proposes that DO inhibits the effects of DM, but we show that DO can interact directly with the MHC II molecule HLA-DR1 (DR1) and have both inhibitory and enhancing effects depending on the affinity of DR1 for the peptide. Based on our observations, DO only regulates peptide association but not dissociation. We constructed a molecular model for the mechanism of DO in which DO binds to the peptide-receptive MHC II molecules that DM generates, either by dissociating the bound peptides, or opening the empty groove. This model was verified through Surface Plasmon Resonance (SPR) experiments in addition to specific peptide-binding studies. We conclude that the role for DO is not to inhibit the function of DM, but rather to enforce it, adding another layer of control on peptide selection.

[发布机构] Johns Hopkins University

[效力级别] Antigen Presentation

[关键词] HLA-DO;Antigen Presentation;MHC Class II;HLA-DM;HLA-DR1;Immunodominance.;Immunology