Human Dendritic Cell Expression of HLA-DO Is Subset Specific and Regulated by Maturation

Abstract

Expression of HLA-DO (DO) in cells that express HLA-DM (DM) results in an altered repertoire of MHC class II/peptide complexes, indicating that DO modulates DM function. Human and murine B cells and thymic epithelial cells express DO, while monocytes/macrophages do not. Monocyte-derived dendritic cells (DC) also have been found to be DO-negative, leading to the assumption that DC do not express DO. In this study, we report that, in fact, certain types of human primary DC express DO. These include Langerhans cells (LC) and some subtypes of circulating blood DC. Specifically, the majority of BDCA-3+ DC, a small subset of uncertain function, are DO+, while smaller proportions of CD11c+, BDCA-1+ (myeloid) DC, at most a minority of CD123+/BDCA-2+ (plasmacytoid) DC, and no detectable CD16+ (myeloid) DC, express DO. Immunohistochemistry of human tonsil sections demonstrates that tonsillar interdigitating DC are also DO+. In a subset of immature LC with higher DO expression, an increased fraction of surface DR molecules carry CLIP peptides, indicating that DO functions as a DM inhibitor in these cells. LC expression of DO is down-regulated by maturation stimuli. DM levels also decrease under these conditions, but the DM:DO ratio generally increases. In the myeloid cell types tested, DO expression correlates with levels of DOβ, but not DOα, implying that modulation of DOβ regulates DO dimer abundance in these cells. The range of APC types shown to express DO suggests a broader role for DO in immune function than previously appreciated.

Posttranslational Regulation ofI-Edby Affinity for CLIP

“…Coexpression of DO can also reduce DM function. DO is found in naive B cells, specific immature DC subsets, medullary thymic epithelial cells, and in cells lining Hassall's corpuscles, a thymic structure involved in selection of regulatory T cells (6,8,9,64,65). These cells are involved in thymic selection and maintenance of peripheral tolerance, suggesting that variation in CLIP affinity also may be influential in establishment and maintenance of tolerance.…”

“…ajor histocompatibility complex class II molecules are polymorphic glycoproteins that are constitutively expressed on professional APCs, including dendritic cells (DC), 6 B cells, and macrophages, and can be induced in other cell types by cytokines (1). Recognition of class II MHC/peptide complexes by TCR is critical for appropriate thymic selection, immune responses to pathogens and tumors, and the maintenance of peripheral tolerance.…”

MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

“…In immature DCs, DO is thought to increase the range of presented peptides, therewith facilitating tolerance induction to a broad range of self peptides (Yi et al 2010). DO expression is down-regulated in activated B cells and DCs, enhancing DMcatalyzed peptide loading under inflammatory conditions (Glazier et al 2002;Hornell et al 2006;Draghi and Denzin 2010;Porter et al 2011).…”

Evidence for a human leucocyte antigen‐DM‐induced structural change in human leucocyte antigen‐DOβ

“…36 Interestingly, the recent demonstrations of DO expression in specific DC subsets argue against a specific role in B cells in the context of the surface immunoglobulin antigen uptake. [37][38][39] Still, it is now accepted that H2-DO and DO 'modulate' MHC class II antigen processing. 32,34,36,40 In human B lymphocytes, as opposed to their mouse counterpart, the majority of DO molecules was found associated with DM 30,36,39,41 and this association allows DO to egress the ER.…”