Immunity & infection
We have reported that the major histocompatibility molecule HLA-DQ2 (DQA1*05:01/DQB1*02:01) is relatively resistant to HLA-DM (DM), a peptide exchange catalyst for MHC class II. Here, we analyzed the role of DQ2/DM interaction in the generation of DQ2-restricted gliadin epitopes, relevant to celiac disease, or DQ2-restricted viral epitopes, relevant to host defense. We used paired antigen presenting cells (APC), differing in DM expression (DMnull vs DMhigh) or differing by expression of wild type DQ2 versus a DM-susceptible, DQ2 point mutant DQ2a+53G. The APC pairs were compared for their ability to stimulate CD4+ T cell clones. Despite higher DQ2 levels, DMhigh APC attenuated T cell responses compared to DMnull APC after intracellular generation of 4 tested gliadin epitopes. DMhigh APC expressing the DQ2a+53G mutant further suppressed these gliadin-mediated responses. The gliadin epitopes were found to have moderate affinity for DQ2, and even lower affinity for the DQ2 mutant, consistent with DM suppression of their presentation. In contrast, DMhigh APC significantly promoted the presentation of DQ2-restricted epitopes derived intracellularly from inactivated herpes simplex virus type 2 (HSV-2), influenza hemagglutinin and human papillomavirus (HPV) E7 protein. When extracellular peptide epitopes were used as antigen, the DQ2 surface levels and peptide affinity were the major regulators of T cell responses. The differential effect of DM on stimulation of the 2 groups of T cell clones implies differences in DQ2 presentation pathways associated with non-pathogen and pathogen-derived antigens in vivo.