HLA-DO

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.[1][2] 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.[3][4][5] 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.[3][6] 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.[6][7][8]

Major Histocompatibility Complex, Class II, DO alpha
Identifiers
SymbolHLA-DOA
Alt. symbolsHLA-DZA, HLA-DNA
NCBI gene3111
HGNC4936
OMIM142930
RefSeqNM_002119
UniProtQ9TQD3
Other data
LocusChr. 6 p21.3
Major Histocompatibility Complex, Class II, DO beta
Identifiers
SymbolHLA-DOB
NCBI gene3112
HGNC4937
OMIM600629
RefSeqNM_002120
UniProtP13765
Other data
LocusChr. 6 p21.3

Discovery

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.[9] 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.[7][8] In contrast to other molecules of MHC class II, interferon gamma does not induce HLA-DO expression.[1]

Function

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.<re[7][3]

During infection, exogenous antigen is internalized by phagocytosis or receptor-mediated endocytosis, and processed in hydrolytic enzyme-containing compartments of increasing acidity.[1][8] 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.[1][8] HLA-DO is strongly associated with HLA-DM throughout the catalyzed exchange.[3]

Structure

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.[4][8][2] 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.[4][9][2] The structure of the free HLA-DO protein, however, remains to be elucidated.[9]

References
  1. 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.
  2. 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.
  3. 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.
  4. 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: 336. doi:10.3389/fimmu.2013.00336. ISSN 1664-3224. PMC 3797982. PMID 24146666.
  5. Chen, Xinjian; Jensen, Peter E. (2014). "Biological function of HLA-DO (H2-O)". Critical Reviews in Immunology. 34 (3): 215–225. doi:10.1615/critrevimmunol.2014009999. ISSN 1040-8401. PMID 24941074.
  6. 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: 465. doi:10.3389/fimmu.2013.00465. ISSN 1664-3224. PMC 3865790. PMID 24381574.
  7. 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. S2CID 41107541.
  8. 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: 319. doi:10.3389/fimmu.2017.00319. ISSN 1664-3224. PMC 5362600. PMID 28386257.
  9. 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.
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