HLA-DO

Studies on HLA-DO transfected fibroblast cells lines and on the HLA-DO mouse homolog, H-2O, provide most of the current knowledge on the protein.{{cite journal | vauthors = Mellins ED, Stern LJ | title = HLA-DM and HLA-DO, key regulators of MHC-II processing and presentation | journal = Current Opinion in Immunology | volume = 26 | pages = 115–22 | date = February 2014 | pmid = 24463216 | pmc = 3944065 | doi = 10.1016/j.coi.2013.11.005 }} In 1985, the α- and β-chains were separately discovered, and in 1990, both chains were found to be co-expressed in one protein in H-2O. In contrast to other molecules of MHC class II, interferon gamma does not induce HLA-DO expression.

During infection, exogenous antigen is internalized by phagocytosis or receptor-mediated endocytosis, and processed in hydrolytic enzyme-containing compartments of increasing acidity.{{cite journal | vauthors = Adler LN, Jiang W, Bhamidipati K, Millican M, Macaubas C, Hung SC, Mellins ED | title = The Other Function: Class II-Restricted Antigen Presentation by B Cells | journal = Frontiers in Immunology | volume = 8 | pages = 319 | date = 2017-03-23 | pmid = 28386257 | pmc = 5362600 | doi = 10.3389/fimmu.2017.00319 | doi-access = free }} To bind to the MHC-class II protein, HLA-DM catalyzes the exchange of CLIP, a protein occupying the binding groove of MHC class II, with the antigenic oligopeptide. HLA-DO is strongly associated with HLA-DM throughout the catalyzed exchange. HLA-DM also plays a role in causing conformational changes in the MHC II groove leading to the release of poor fitting, or “DM-sensitive”, peptides to encourage the presentation of higher affinity peptides.{{cite journal | vauthors = Welsh RA, Sadegh-Nasseri S | title = The love and hate relationship of HLA-DM/DO in the selection of immunodominant epitopes | journal = Current Opinion in Immunology | volume = 64 | pages = 117–123 | date = June 2020 | pmid = 32599219 | pmc = 7762731 | doi = 10.1016/j.coi.2020.05.007 }}

Unlike classical MHC II proteins, but like HLA-DM, HLA-DO does not bind processed oligopeptides of antigen.{{cite journal | vauthors = Liljedahl M, Kuwana T, Fung-Leung WP, Jackson MR, Peterson PA, Karlsson L | title = HLA-DO is a lysosomal resident which requires association with HLA-DM for efficient intracellular transport | journal = The EMBO Journal | volume = 15 | issue = 18 | pages = 4817–24 | date = September 1996 | pmid = 8890155 | doi = 10.1002/j.1460-2075.1996.tb00862.x | pmc = 452218 }} Rather, HLA-DO binds a fellow non-classical MHC II protein HLA-DM at the MHC class II at the peptide-exchange catalysis site suggesting that it acts as a regulator of sorts. Further suggesting the tangential function of DO and DM, the movement of DO from the endoplasmic reticulum to the site of MHC II processing is completely dependent on the association of DO with DM.

Recent studies into the mechanisms of the less studied HLA-DO suggest that it may work in regulatory fashion on the ability of HLA-DM to choose immunodominant epitopes presented in the thymus. An in vivo study using mice with an HLA-DO knockout lead to an increased disposition for self-reactive immune disease. Research suggests that this may be due to a lack of HLA-DO as a regulator of HLA-DM as a DO knockout leads to less diversity in the MHC II binding as only HLA-DM insensitive peptides will remain bound to the groove.{{cite journal | vauthors = Zwart W, Griekspoor A, Kuijl C, Marsman M, van Rheenen J, Janssen H, Calafat J, van Ham M, Janssen L, van Lith M, Jalink K, Neefjes J | display-authors = 6 | title = Spatial separation of HLA-DM/HLA-DR interactions within MIIC and phagosome-induced immune escape | journal = Immunity | volume = 22 | issue = 2 | pages = 221–33 | date = February 2005 | pmid = 15723810 | doi = 10.1016/S0960-9822(06)00414-3 | s2cid = 16642599 | doi-access = free }}{{cite journal | vauthors = Nanaware PP, Jurewicz MM, Leszyk JD, Shaffer SA, Stern LJ | title = HLA-DO Modulates the Diversity of the MHC-II Self-peptidome | journal = Molecular & Cellular Proteomics | volume = 18 | issue = 3 | pages = 490–503 | date = March 2019 | pmid = 30573663 | pmc = 6398211 | doi = 10.1074/mcp.RA118.000956 | doi-access = free }} Similarly, HLA-DO is expressed in B cells as well which indicates the possibility of fine tuning the ability of B cells to present a variety of immunodominant epitopes, as opposed to only well fitting peptides unaffected by DM.

Before the three-dimensional structure of complexed HLA-DO was elucidated by X-ray crystallography, its crystal structure was modeled after homology studies to classical MHC class II proteins.{{cite journal | vauthors = Pos W, Sethi DK, Wucherpfennig KW | title = Mechanisms of peptide repertoire selection by HLA-DM | journal = Trends in Immunology | volume = 34 | issue = 10 | pages = 495–501 | date = October 2013 | pmid = 23835076 | pmc = 3796002 | doi = 10.1016/j.it.2013.06.002 }} Following crystallization of the protein, HLA-DO was found to be conformationally similar to classical MHC class II protein, with alterations in the N-terminus. The structure of the free HLA-DO protein, however, remains to be elucidated.

{{Reflist|32em}}

{{Surface antigens}}

Category:MHC class II