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Cited by 87Tuberculosis Research and EpidemiologyImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

Endosomal MR1 trafficking plays a key role in presentation of mycobacterium tuberculosis ligands to MAIT cells

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Harriff, Melanie J., Karamooz, Elham, Burr, Ansen, Grant, Wilmon F., Canfield, Elizabeth T., Sorensen, Michelle L., Moita, Luis F., Lewinsohn, David M.·2016·PLOS Pathogens
DOI 10.1371/journal.ppat.1005524PMC PMC4816560
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Abstract

Mucosal-Associated Invariant T (MAIT) cells, present in high frequency in airway and other mucosal tissues, have Th1 effector capacity positioning them to play a critical role in the early immune response to intracellular pathogens, including Mycobacterium tuberculosis (Mtb). MR1 is a highly conserved Class I-like molecule that presents vitamin B metabolites to MAIT cells. The mechanisms for loading these ubiquitous small molecules are likely to be tightly regulated to prevent inappropriate MAIT cell activation. To define the intracellular localization of MR1, we analyzed the distribution of an MR1-GFP fusion protein in antigen presenting cells. We found that MR1 localized to endosomes and was translocated to the cell surface upon addition of 6-formyl pterin (6-FP). To understand the mechanisms by which MR1 antigens are presented, we used a lentiviral shRNA screen to identify trafficking molecules that are required for the presentation of Mtb antigen to HLA-diverse T cells. We identified Stx18, VAMP4, and Rab6 as trafficking molecules regulating MR1-dependent MAIT cell recognition of Mtb-infected cells. Stx18 but not VAMP4 or Rab6 knockdown also resulted in decreased 6-FP-dependent surface translocation of MR1 suggesting distinct pathways for loading of exogenous ligands and intracellular mycobacterially-derived ligands. We postulate that endosome-mediated trafficking of MR1 allows for selective sampling of the intracellular environment.

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  • MR1 mostly traffics intracellularly within LAMP1+ late endosomes/lysosomes.

    “Although MR1 mostly traffics intracellularly within LAMP1+ late endosomes/lysosomes, 32 , 33”

    From The MR1/MAIT cell axis enhances dystrophic neurite development in Alzheimer's disease (2025) · cites this paper as [32]

    The Results section ('MR1 localizes to vesicular compartments with late endosome and lysosome markers'; page not provided) says most observed MR1 was intracellular. It says only subsets of MR1-positive endosomal compartments co-localized with Lamp1 and other late-endosome or lysosome markers, while MR1 was also observed in an ER-like compartment. It therefore does not establish that MR1 is mostly within Lamp1-positive late endosomes or lysosomes. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 34

  1. [1]Dusseaux M, Martin E, Serriari N, Peguillet I, Premel V, Louis D, et al Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells. Blood. 2011; 117(4): 1250– 9. Epub 2010/11/19. 10.1182/blood-2010-08-303339. 21084709 · DOI
  2. [2]Treiner E, Duban L, Bahram S, Radosavljevic M, Wanner V, Tilloy F, et al Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature. 2003; 422(6928): 164– 9. Epub 2003/03/14. 10.1038/nature01433. 12634786 · DOI · Paper page
  3. [3]Gold MC, Cerri S, Smyk-Pearson S, Cansler ME, Vogt TM, Delepine J, et al Human mucosal associated invariant T cells detect bacterially infected cells. PLoS Biol. 2010; 8(6): e1000407 Epub 2010/07/09. 10.1371/journal.pbio.1000407 20613858 PMC2893946 · DOI
  4. [4]Le Bourhis L, Martin E, Peguillet I, Guihot A, Froux N, Core M, et al Antimicrobial activity of mucosal-associated invariant T cells. Nat Immunol. 2010; 11(8): 701– 8. Epub 2010/06/29. 10.1038/ni.1890. 20581831 · DOI
  5. [5]Meierovics A, Yankelevich WJ, Cowley SC. MAIT cells are critical for optimal mucosal immune responses during in vivo pulmonary bacterial infection. Proc Natl Acad Sci U S A. 2013; 110(33): E3119– 28. Epub 2013/07/31. 10.1073/pnas.1302799110 23898209 PMC3746930 · DOI
  6. [6]Chua WJ, Truscott SM, Eickhoff CS, Blazevic A, Hoft DF, Hansen TH. Polyclonal mucosa-associated invariant T cells have unique innate functions in bacterial infection. Infect Immun. 2012; 80(9): 3256– 67. Epub 2012/07/11. 10.1128/IAI.00279-12 22778103 PMC3418730 · DOI
  7. [7]Georgel P, Radosavljevic M, Macquin C, Bahram S. The non-conventional MHC class I MR1 molecule controls infection by Klebsiella pneumoniae in mice. Molecular immunology. 2011; 48(5): 769– 75. Epub 2010/12/31. 10.1016/j.molimm.2010.12.002. 21190736 · DOI
  8. [8]Huang S, Martin E, Kim S, Yu L, Soudais C, Fremont DH, et al MR1 antigen presentation to mucosal-associated invariant T cells was highly conserved in evolution. Proc Natl Acad Sci U S A. 2009; 106(20): 8290– 5. Epub 2009/05/07. 10.1073/pnas.0903196106 19416870 PMC2688861 · DOI
  9. [9]Riegert P, Wanner V, Bahram S. Genomics, isoforms, expression, and phylogeny of the MHC class I-related MR1 gene. J Immunol. 1998; 161(8): 4066– 77. Epub 1998/10/21.. 9780177
  10. [10]Huang S, Gilfillan S, Kim S, Thompson B, Wang X, Sant AJ, et al MR1 uses an endocytic pathway to activate mucosal-associated invariant T cells. J Exp Med. 2008; 205(5): 1201– 11. Epub 2008/04/30. 10.1084/jem.20072579 18443227 PMC2373850 · DOI
  11. [11]Kjer-Nielsen L, Patel O, Corbett AJ, Le Nours J, Meehan B, Liu L, et al MR1 presents microbial vitamin B metabolites to MAIT cells. Nature. 2012; 491(7426): 717– 23. Epub 2012/10/12. 10.1038/nature11605. 23051753 · DOI · Paper page
  12. [12]Eckle SB, Birkinshaw RW, Kostenko L, Corbett AJ, McWilliam HE, Reantragoon R, et al A molecular basis underpinning the T cell receptor heterogeneity of mucosal-associated invariant T cells. J Exp Med. 2014; 211(8): 1585– 600. 10.1084/jem.20140484 25049336 PMC4113946 · DOI
  13. [13]Corbett AJ, Eckle SB, Birkinshaw RW, Liu L, Patel O, Mahony J, et al T-cell activation by transitory neo-antigens derived from distinct microbial pathways. Nature. 2014 Epub 2014/04/04. 10.1038/nature13160. 24695216 · DOI
  14. [14]Harriff MJ, Cansler ME, Toren KG, Canfield ET, Kwak S, Gold MC, et al Human lung epithelial cells contain Mycobacterium tuberculosis in a late endosomal vacuole and are efficiently recognized by CD8(+) T cells. PLoS One. 2014; 9(5): e97515 Epub 2014/05/16. 10.1371/journal.pone.0097515 24828674 PMC4020835 · DOI
  15. [15]Huang S, Gilfillan S, Cella M, Miley MJ, Lantz O, Lybarger L, et al Evidence for MR1 antigen presentation to mucosal-associated invariant T cells. J Biol Chem. 2005; 280(22): 21183– 93. Epub 2005/04/02. 10.1074/jbc.M501087200. 15802267 · DOI
  16. [16]Hatsuzawa K, Hirose H, Tani K, Yamamoto A, Scheller RH, Tagaya M. Syntaxin 18, a SNAP receptor that functions in the endoplasmic reticulum, intermediate compartment, and cis-Golgi vesicle trafficking. J Biol Chem. 2000; 275(18): 13713– 20. Epub 2000/05/02.. 10788491
  17. [17]Hatsuzawa K, Tamura T, Hashimoto H, Hashimoto H, Yokoya S, Miura M, et al Involvement of syntaxin 18, an endoplasmic reticulum (ER)-localized SNARE protein, in ER-mediated phagocytosis. Mol Biol Cell. 2006; 17(9): 3964– 77. Epub 2006/06/23. 10.1091/mbc.E05-12-1174 16790498 PMC1593171 · DOI
  18. [18]Okumura AJ, Hatsuzawa K, Tamura T, Nagaya H, Saeki K, Okumura F, et al Involvement of a novel Q-SNARE, D12, in quality control of the endomembrane system. J Biol Chem. 2006; 281(7): 4495– 506. Epub 2005/12/16. 10.1074/jbc.M509715200. 16354670 · DOI
  19. [19]Hong W. SNAREs and traffic. Biochim Biophys Acta. 2005; 1744(3): 493– 517.. 16038056
  20. [20]Aoki T, Kojima M, Tani K, Tagaya M. Sec22b-dependent assembly of endoplasmic reticulum Q-SNARE proteins. The Biochemical journal. 2008; 410(1): 93– 100. Epub 2007/11/06. 10.1042/BJ20071304. 17979832 · DOI
  21. [21]Iinuma T, Aoki T, Arasaki K, Hirose H, Yamamoto A, Samata R, et al Role of syntaxin 18 in the organization of endoplasmic reticulum subdomains. J Cell Sci. 2009; 122(Pt 10): 1680– 90. 10.1242/jcs.036103. 19401338 · DOI
  22. [22]Shitara A, Shibui T, Okayama M, Arakawa T, Mizoguchi I, Sakakura Y, et al VAMP4 is required to maintain the ribbon structure of the Golgi apparatus. Molecular and cellular biochemistry. 2013; 380(1–2): 11– 21. 10.1007/s11010-013-1652-4 23677696 PMC3695666 · DOI
  23. [23]Sun Y, Shestakova A, Hunt L, Sehgal S, Lupashin V, Storrie B. Rab6 regulates both ZW10/RINT-1 and conserved oligomeric Golgi complex-dependent Golgi trafficking and homeostasis. Mol Biol Cell. 2007; 18(10): 4129– 42. 10.1091/mbc.E07-01-0080 17699596 PMC1995728 · DOI
  24. [24]Gold MC, McLaren JE, Reistetter JA, Smyk-Pearson S, Ladell K, Swarbrick GM, et al MR1-restricted MAIT cells display ligand discrimination and pathogen selectivity through distinct T cell receptor usage. J Exp Med. 2014; 211(8): 1601– 10. Epub 2014/07/23. 10.1084/jem.20140507 25049333 PMC4113934 · DOI
  25. [25]Neefjes J, Jongsma ML, Paul P, Bakke O. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol. 2011; 11(12): 823– 36. Epub 2011/11/15. 10.1038/nri3084. 22076556 · DOI · Paper page
  26. [26]Shen L, Sigal LJ, Boes M, Rock KL. Important role of cathepsin S in generating peptides for TAP-independent MHC class I crosspresentation in vivo. Immunity. 2004; 21(2): 155– 65. 10.1016/j.immuni.2004.07.004. 15308097 · DOI
  27. [27]Barral DC, Brenner MB. CD1 antigen presentation: how it works. Nat Rev Immunol. 2007; 7(12): 929– 41. 10.1038/nri2191. 18037897 · DOI
  28. [28]Moody DB, Porcelli SA. Intracellular pathways of CD1 antigen presentation. Nat Rev Immunol. 2003; 3(1): 11– 22. 10.1038/nri979. 12511872 · DOI
  29. [29]Soudais C, Samassa F, Sarkis M, Le Bourhis L, Bessoles S, Blanot D, et al In Vitro and In Vivo Analysis of the Gram-Negative Bacteria-Derived Riboflavin Precursor Derivatives Activating Mouse MAIT Cells. J Immunol. 2015 10.4049/jimmunol.1403224. 25870247 · DOI
  30. [30]Grotzke JE, Siler AC, Lewinsohn DA, Lewinsohn DM. Secreted immunodominant Mycobacterium tuberculosis antigens are processed by the cytosolic pathway. J Immunol. 2010; 185(7): 4336– 43. Epub 2010/08/31. 10.4049/jimmunol.1000801 20802151 PMC2988655 · DOI
  31. [31]Heinzel AS, Grotzke JE, Lines RA, Lewinsohn DA, McNabb AL, Streblow DN, et al HLA-E-dependent presentation of Mtb-derived antigen to human CD8+ T cells. J Exp Med. 2002; 196(11): 1473– 81. Epub 2002/12/04. 12461082 PMC2194265
  32. [32]Lewinsohn DM, Grotzke JE, Heinzel AS, Zhu L, Ovendale PJ, Johnson M, et al Secreted proteins from Mycobacterium tuberculosis gain access to the cytosolic MHC class-I antigen-processing pathway. J Immunol. 2006; 177(1): 437– 42. Epub 2006/06/21. doi: 177/1/437 [pii].. 16785540
  33. [33]Lewinsohn DM, Briden AL, Reed SG, Grabstein KH, Alderson MR. Mycobacterium tuberculosis-reactive CD8+ T lymphocytes: the relative contribution of classical versus nonclassical HLA restriction. J Immunol. 2000; 165(2): 925– 30. Epub 2000/07/06. doi: ji_v165n2p925 [pii].. 10878367
  34. [34]Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001; 25(4): 402– 8. Epub 2002/02/16. 10.1006/meth.2001.1262. 11846609 · DOI · Paper page

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Authors
Harriff, M. J., Karamooz, E., Burr, A., Grant, W. F., Canfield, E. T., Sorensen, M. L., Moita, L. F., & Lewinsohn, D. M.
Affiliations
  • Oregon Health & Science University (US)
  • Portland VA Medical Center (US)
Corresponding author
  • Harriff, Melanie J.
  • Lewinsohn, David M.
ORCID
Venue
PLOS Pathogens
Publisher
Public Library of Science (PLoS)
Published
2016-03-31
Volume
12
Issue
3
Pages
e1005524
ISSN
  • 1553-7366 (ISSN-L)
  • 1553-7374
DOI
10.1371/journal.ppat.1005524
PMC
PMC4816560
OpenAlex
W2327739049
Cited by
87
References
0
Citations by year
2026: 11 · 2025: 8 · 2024: 5 · 2023: 7 · 2022: 10 · 2021: 6 · 2020: 13 · 2019: 7 · 2018: 12 · 2017: 5 · 2016: 3
FWCI
8.31
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Pathogens (publishedVersion, public-domain)
  • Europe PMC (PubMed Central) (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • U.S. Department of Veterans Affairs (BX000533, I01BX000533, IK2 CX000538)
  • American Lung Association
  • National Heart, Lung, and Blood Institute (T32HL083808)
  • National Institute of Allergy and Infectious Diseases (R01AI048090, U01AI095776)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
MR1, mucosal-associated invariant T cells, Mycobacterium tuberculosis, endosomal trafficking, antigen presentation, VAMP4, Rab6, antigen loading, antigen-presenting cells
MeSH terms
Humans, Lymphocyte Activation, Mucous Membrane, Mycobacterium tuberculosis, Endosomes, Histocompatibility Antigens Class I, Minor Histocompatibility Antigens, T-Lymphocyte Subsets, Receptors, Antigen, T-Cell, alpha-beta, Antigen Presentation, Protein Transport

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