HLA-DO

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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
Search for
StructuresSwiss-model
DomainsInterPro
Major Histocompatibility Complex, Class II, DO beta
Identifiers
SymbolHLA-DOB
NCBI gene3112
HGNC4937
OMIM600629
RefSeqNM_002120
UniProtP13765
Other data
LocusChr. 6 p21.3
Search for
StructuresSwiss-model
DomainsInterPro

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] Although HLA-DM can be found without HLA-DO, HLA-DO is only found in complex with HLA-DM and exhibits instability in the absence of HLA-DM. The evolutionary conservation of both DM and DO, further denote its biological significance and potential to confer evolutionary benefits to its host.[6][7][8]

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

During infection, exogenous antigen is internalized by phagocytosis or receptor-mediated endocytosis, and processed in hydrolytic enzyme-containing compartments of increasing acidity.[1][10] 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.[11]

Unlike classical MHC II proteins, but like HLA-DM, HLA-DO does not bind processed oligopeptides of antigen.[12] 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.[12]

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.[11] An in vivo study using mice with an HLA-DO knockout lead to an increased disposition for self-reactive immune disease.[11] 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.[13][11][14] 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.[10]

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. ^ a b c 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. ^ a b c Pos W, Sethi DK, Wucherpfennig KW (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. PMC 3796002. PMID 23835076.
  3. ^ a b Poluektov YO, Kim A, Hartman IZ, Sadegh-Nasseri S (2013-08-08). "HLA-DO as the optimizer of epitope selection for MHC class II antigen presentation". PLOS ONE. 8 (8): e71228. Bibcode:2013PLoSO...871228P. doi:10.1371/journal.pone.0071228. PMC 3738515. PMID 23951115.
  4. ^ a b c Yin L, Stern LJ (October 2013). "HLA-DM Focuses on Conformational Flexibility Around P1 Pocket to Catalyze Peptide Exchange". Frontiers in Immunology. 4: 336. doi:10.3389/fimmu.2013.00336. PMC 3797982. PMID 24146666.
  5. ^ Chen X, Jensen PE (2014). "Biological function of HLA-DO (H2-O)". Critical Reviews in Immunology. 34 (3): 215–25. doi:10.1615/critrevimmunol.2014009999. PMID 24941074.
  6. ^ a b Denzin LK (December 2013). "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. PMC 3865790. PMID 24381574.
  7. ^ a b 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. ^ a b c Adler LN, Jiang W, Bhamidipati K, Millican M, Macaubas C, Hung SC, Mellins ED (March 2017). "The Other Function: Class II-Restricted Antigen Presentation by B Cells". Frontiers in Immunology. 8: 319. doi:10.3389/fimmu.2017.00319. PMC 5362600. PMID 28386257.
  9. ^ a b c 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.
  10. ^ a b Adler LN, Jiang W, Bhamidipati K, Millican M, Macaubas C, Hung SC, Mellins ED (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. PMC 5362600. PMID 28386257.
  11. ^ a b c d Welsh RA, Sadegh-Nasseri S (June 2020). "The love and hate relationship of HLA-DM/DO in the selection of immunodominant epitopes". Current Opinion in Immunology. 64: 117–123. doi:10.1016/j.coi.2020.05.007. PMC 7762731. PMID 32599219.
  12. ^ a b Liljedahl M, Kuwana T, Fung-Leung WP, Jackson MR, Peterson PA, Karlsson L (September 1996). "HLA-DO is a lysosomal resident which requires association with HLA-DM for efficient intracellular transport". The EMBO Journal. 15 (18): 4817–24. doi:10.1002/j.1460-2075.1996.tb00862.x. PMC 452218. PMID 8890155.
  13. ^ Zwart W, Griekspoor A, Kuijl C, Marsman M, van Rheenen J, Janssen H, et al. (February 2005). "Spatial separation of HLA-DM/HLA-DR interactions within MIIC and phagosome-induced immune escape". Immunity. 22 (2): 221–33. doi:10.1016/S0960-9822(06)00414-3. PMID 15723810. S2CID 16642599.
  14. ^ Nanaware PP, Jurewicz MM, Leszyk JD, Shaffer SA, Stern LJ (March 2019). "HLA-DO Modulates the Diversity of the MHC-II Self-peptidome". Molecular & Cellular Proteomics. 18 (3): 490–503. doi:10.1074/mcp.RA118.000956. PMC 6398211. PMID 30573663.
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