Human leukocyte histocompatibility complex DO (HLA-DO) is an intracellular, dimeric non-classical Major Histocompatibility Complex (MHC) class II protein composed of α- and β-subunits which interact with HLA-DM in order to fine tune immunodominant epitope selection. As a non-classical MHC class II molecule, HLA-DO is a non-polymorphic accessory protein that aids in antigenic peptide chaperoning and loading, as opposed to its classical counterparts, which are polymorphic and involved in antigen presentation. Though more remains to be elucidated about the function of HLA-DO, its unique distribution in the mammalian body—namely, the exclusive expression of HLA-DO in B cells, thymic medullary epithelial cells, and dendritic cells—indicate that it may be of physiological importance and has inspired further research. Moreover, HLA-DO is stable in complex with HLA-DM, and its exhibited instability in the absence of HLA-DM, as well as its evolutionary conservation, further denote its biological significance and potential to confer evolutionary benefits to its host.
|Major Histocompatibility Complex, Class II, DO alpha|
|Alt. symbols||HLA-DZA, HLA-DNA|
|Locus||Chr. 6 p21.3|
|Major Histocompatibility Complex, Class II, DO beta|
|Locus||Chr. 6 p21.3|
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. 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.
The binding of HLA-DO at the MHC class II peptide-exchange catalysis site suggested that it acts as a competitive inhibitor, although biochemical studies have established its complementary function to HLA-DM in fine tuning epitope selection.
During infection, exogenous antigen is internalized by phagocytosis or receptor-mediated endocytosis, and processed in hydrolytic enzyme-containing compartments of increasing acidity. Once the degraded antigen is 13-18 residues, it is ready to bind to MHC class II molecules. 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.
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. 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.
- Owen JA, Punt J, Stranford SA, Jones PP, Kuby J (2013). Kuby immunology (7th ed.). New York: W.H. Freeman. ISBN 978-1-4641-1991-0. OCLC 820117219.
- Pos, Wouter; Sethi, Dhruv K.; Wucherpfennig, Kai W. (October 2013). "Mechanisms of Peptide Repertoire Selection by HLA-DM". Trends in Immunology. 34 (10): 495–501. doi:10.1016/j.it.2013.06.002. ISSN 1471-4906. PMC 3796002. PMID 23835076.
- Poluektov YO, Kim A, Sadegh-Nasseri S (September 2013). "HLA-DO and Its Role in MHC Class II Antigen Presentation". Frontiers in Immunology. 4: 260. doi:10.3389/fimmu.2013.00260. PMC 3756479. PMID 24009612.
- Yin, Liusong; Stern, Lawrence J. (2013-10-17). "HLA-DM Focuses on Conformational Flexibility Around P1 Pocket to Catalyze Peptide Exchange". Frontiers in Immunology. 4. doi:10.3389/fimmu.2013.00336. ISSN 1664-3224. PMC 3797982. PMID 24146666.
- Chen, Xinjian; Jensen, Peter E. (2014). "Biological function of HLA-DO (H2-O)". Critical Reviews in Immunology. 34 (3): 215–225. ISSN 1040-8401. PMID 24941074.
- Denzin, Lisa K. (2013-12-17). "Inhibition of HLA-DM Mediated MHC Class II Peptide Loading by HLA-DO Promotes Self Tolerance". Frontiers in Immunology. 4. doi:10.3389/fimmu.2013.00465. ISSN 1664-3224. PMC 3865790. PMID 24381574.
- Chen X, Jensen PE (June 2004). "The expression of HLA-DO (H2-O) in B lymphocytes". Immunologic Research. 29 (1–3): 19–28. doi:10.1385/IR:29:1-3:019. PMID 15181267.
- Adler, Lital N.; Jiang, Wei; Bhamidipati, Kartik; Millican, Matthew; Macaubas, Claudia; Hung, Shu-chen; Mellins, Elizabeth D. (2017-03-23). "The Other Function: Class II-Restricted Antigen Presentation by B Cells". Frontiers in Immunology. 8. doi:10.3389/fimmu.2017.00319. ISSN 1664-3224. PMC 5362600. PMID 28386257.
- Mellins ED, Stern LJ (February 2014). "HLA-DM and HLA-DO, key regulators of MHC-II processing and presentation". Current Opinion in Immunology. 26: 115–22. doi:10.1016/j.coi.2013.11.005. PMC 3944065. PMID 24463216.