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ACS Chemical Biology
treated with bafilomycin A1. It is unknown yet if agonists from thank A. Sewell, Cardiff University School of Medicine, for
1
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the bacteria are loaded onto endosomal MR1 molecules, or if
localization of bacteria within these compartments simply
provides a highly concentrated pool of agonists that then traffic
to the ER for presentation. In contrast, presentation of agonists
derived from prodrug 10 is compromized if MR1 is prevented
from internalizing into recycling endosomes. It remains to be
established whether presentation via MR1 in recycling
endosomal molecules, as opposed to the ER (the predominant
route for 5-A-RU and 5-OP-RU), leads to qualitatively different
MAIT cell responses. A prodrug like 10 could be used to
investigate this possibility. The fact that 10 would be presented
without additional bacteria-derived signals, such as toll-like
receptors, would enable the MR1-antigen presentation axis to
be studied in isolation. Lastly, the prodrug design and proof of
concept reported here opens the door for further chemical
modifications, such as attaching a reporter, or attaching
targeting and/or other modifying groups to further explore
MAIT cell biology in vitro or in vivo.
supplying the MR1-negative THP-1 cells. The MR1 tetramer
technology used was developed jointly by J. McCluskey, J.
Rossjohn, and D. Fairlie, and the material was produced by the
NIH Tetramer Core Facility as permitted to be distributed by
the University of Melbourne.
ABBREVIATIONS
REFERENCES
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1.
Kjer-Nielsen, L.; Patel, O.; Corbett, A. J.; Le Nours, J.; Meehan,
B.; Liu, L.; Bhati, M.; Chen, Z.; Kostenko, L.; Reantragoon, R.;
Williamson, N. A.; Purcell, A. W.; Dudek, N. L.; McConville, M. J.; O'Hair,
R. A.; Khairallah, G. N.; Godfrey, D. I.; Fairlie, D. P.; Rossjohn, J.;
McCluskey, J., MR1 presents microbial vitamin B metabolites to MAIT
cells. Nature 2012, 491, 717-723.
2.
Lepore, M.; Kalinichenko, A.; Colone, A.; Paleja, B.; Singhal,
A.; Tschumi, A.; Lee, B.; Poidinger, M.; Zolezzi, F.; Quagliata, L.; Sander,
P.; Newell, E.; Bertoletti, A.; Terracciano, L.; De Libero, G.; Mori, L.,
Parallel T-cell cloning and deep sequencing of human MAIT cells reveal
stable oligoclonal TCRbeta repertoire. Nat Commun 2014, 5, No.3866.
ASSOCIATED CONTENT
Supporting Information. Synthetic procedures and analytical
data for vaccine synthesis, the material and methods for the
biological experiments and supplementary figures are available
3.
Meierovics, A. I.; Cowley, S. C., MAIT cells promote
inflammatory monocyte differentiation into dendritic cells during
pulmonary intracellular infection. J. Exp. Med. 2016, 213, 2793-2809.
4.
Keller, A. N.; Eckle, S. B.; Xu, W.; Liu, L.; Hughes, V. A.; Mak,
J. Y.; Meehan, B. S.; Pediongco, T.; Birkinshaw, R. W.; Chen, Z.; Wang,
H.; D'Souza, C.; Kjer-Nielsen, L.; Gherardin, N. A.; Godfrey, D. I.;
Kostenko, L.; Corbett, A. J.; Purcell, A. W.; Fairlie, D. P.; McCluskey, J.;
Rossjohn, J., Drugs and drug-like molecules can modulate the function of
mucosal-associated invariant T cells. Nat. Immunol. 2017, 18, 402-411.
AUTHOR INFORMATION
Corresponding Author
5.
Gold, M. C.; Cerri, S.; Smyk-Pearson, S.; Cansler, M. E.; Vogt,
T. M.; Delepine, J.; Winata, E.; Swarbrick, G. M.; Chua, W.-J.; Yu, Y. Y.
L.; Lantz, O.; Cook, M. S.; Null, M. D.; Jacoby, D. B.; Harriff, M. J.;
Lewinsohn, D. A.; Hansen, T. H.; Lewinsohn, D. M., Human Mucosal
Associated Invariant T Cells Detect Bacterially Infected Cells. PLoS Biol.
2010, 8, e1000407.
Present Addresses
†If an author’s address is different than the one given in the
affiliation line, this information may be included here.
6.
Rouxel, O.; Da Silva, J.; Beaudoin, L.; Nel, I.; Tard, C.;
Author Contributions
Cagninacci, L.; Kiaf, B.; Oshima, M.; Diedisheim, M.; Salou, M.; Corbett,
A.; Rossjohn, J.; McCluskey, J.; Scharfmann, R.; Battaglia, M.; Polak, M.;
Lantz, O.; Beltrand, J.; Lehuen, A., Cytotoxic and regulatory roles of
mucosal-associated invariant T cells in type 1 diabetes. Nat. Immunol. 2017,
18, 1321-1331.
R.J.A. was primarily responsible for the chemical synthesis,
stability studies and compound characterization components of
the work with contributions from A.J.M. and T.S.B. J.L was
primarily responsible for the in vitro and in vivo analyses with
contributions from O.G., M.S. and V. C. S.T.S.C carried out
biochemical analyses. G.F.P. led the chemical component of the
investigation whilst I.F.H. led the immunological studies. The
manuscript was drafted with editorial contributions from all
authors. All authors have given approval to the final version of the
manuscript. ‡These authors contributed equally.
7.
Magalhaes, I.; Pingris, K.; Poitou, C.; Bessoles, S.; Venteclef,
N.; Kiaf, B.; Beaudoin, L.; Da Silva, J.; Allatif, O.; Rossjohn, J.; Kjer-
Nielsen, L.; McCluskey, J.; Ledoux, S.; Genser, L.; Torcivia, A.; Soudais,
C.; Lantz, O.; Boitard, C.; Aron-Wisnewsky, J.; Larger, E.; Clement, K.;
Lehuen, A., Mucosal-associated invariant T cell alterations in obese and
type 2 diabetic patients. J. Clin. Invest. 2015, 125, 1752-1762.
8.
Carolan, E.; Tobin, L. M.; Mangan, B. A.; Corrigan, M.;
Gaoatswe, G.; Byrne, G.; Geoghegan, J.; Cody, D.; O'Connell, J.; Winter,
D. C.; Doherty, D. G.; Lynch, L.; O'Shea, D.; Hogan, A. E., Altered
distribution and increased IL-17 production by mucosal-associated
invariant T cells in adult and childhood obesity. J. Immunol. 2015, 194,
5775-5780.
Conflict of Interest
Funding Sources
9.
Salio, M.; Gasser, O.; Gonzalez-Lopez, C.; Martens, A.;
Veerapen, N.; Gileadi, U.; Verter, J. G.; Napolitani, G.; Anderson, R.;
Painter, G.; Besra, G. S.; Hermans, I. F.; Cerundolo, V., Activation of
Human Mucosal-Associated Invariant T Cells Induces CD40L-Dependent
Maturation of Monocyte-Derived and Primary Dendritic Cells. J. Immunol.
2017, 199, 2631-2638.
This work was financially supported by the New Zealand
Ministry of Business Innovation and Employment
(RTVU1603), The New Zealand Health Research Council
(HRC 14/502). J.L. was supported by a Maurice Capstick
award. M.S., C.G.L. and V.C. were supported by the MRC HIU
core fund and CRUK (Programme Grant C399/A2291 to V.C.).
10.
McWilliam, H. E.; Eckle, S. B.; Theodossis, A.; Liu, L.; Chen,
Z.; Wubben, J. M.; Fairlie, D. P.; Strugnell, R. A.; Mintern, J. D.;
McCluskey, J.; Rossjohn, J.; Villadangos, J. A., The intracellular pathway
for the presentation of vitamin B-related antigens by the antigen-presenting
molecule MR1. Nat. Immunol. 2016, 17, 531-537.
Notes
11.
Corbett, A. J.; Eckle, S. B.; Birkinshaw, R. W.; Liu, L.; Patel,
ACKNOWLEDGMENT
O.; Mahony, J.; Chen, Z.; Reantragoon, R.; Meehan, B.; Cao, H.;
Williamson, N. A.; Strugnell, R. A.; Van Sinderen, D.; Mak, J. Y.; Fairlie,
D. P.; Kjer-Nielsen, L.; Rossjohn, J.; McCluskey, J., T-cell activation by
transitory neo-antigens derived from distinct microbial pathways. Nature
2014, 509, 361-365.
We thank the BRU and Hugh Green Cytometry Core at the
Malaghan Institute of Medical Research for their technical
support. We thank C. Waugh and the WIMM Flow Cytometry
facility for MAIT and THP1 cell sorting. We would like to
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