Epitope Selection for HLA-DQ2 Presentation: Implications for Celiac Disease and Viral Defense.

Abstract

We have reported that the major histocompatibility molecule HLA-DQ2 (DQA1*05:01/DQB1*02:01) (DQ2) is relatively resistant to HLA-DM (DM), a peptide exchange catalyst for MHC class II. In this study, 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 human APC, differing in DM expression (DMnull versus DMhigh) or differing by expression of wild-type DQ2, versus a DM-susceptible, DQ2 point mutant DQ2α+53G. The APC pairs were compared for their ability to stimulate human CD4+ T cell clones. Despite higher DQ2 levels, DMhigh APC attenuated T cell responses compared with DMnull APC after intracellular generation of four tested gliadin epitopes. DMhigh APC expressing the DQ2α+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 HSV type 2, influenza hemagglutinin, and human papillomavirus E7 protein. When extracellular peptide epitopes were used as Ag, the DQ2 surface levels and peptide affinity were the major regulators of T cell responses. The differential effect of DM on stimulation of the two groups of T cell clones implies differences in DQ2 presentation pathways associated with nonpathogen- and pathogen-derived Ags in vivo.

• Authors: Shu-Chen Hung, Tieying Hou, Wei Jiang, Nan Wang, Shuo-Wang Qiao, I-Ting Chow, Xiaodan Liu, Sjoerd H van der Burg, David M Koelle, William W Kwok, Ludvig M Sollid, Elizabeth D Mellins
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 202 Issue 9 Pg. 2558-2569 (05 01 2019) ISSN: 1550-6606 [Electronic] United States
• PMID: 30926644 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 by The American Association of Immunologists, Inc.

Chemical References

• Epitopes, T-Lymphocyte
• HLA-DQ Antigens
• HLA-DQ2 antigen
• Viral Proteins
• Gliadin

Topics

• Antigen Presentation
• Antigen-Presenting Cells (immunology, pathology)
• CD4-Positive T-Lymphocytes (immunology, pathology)
• Celiac Disease (immunology, pathology)
• Cell Line
• Epitopes, T-Lymphocyte (immunology)
• Gliadin (immunology)
• HLA-DQ Antigens (immunology)
• Humans
• Viral Proteins (immunology)
• Virus Diseases (immunology)