T-cell activation by transitory neo-antigens derived from distinct microbial pathways

Corbett, Alexandra J., Eckle, Sidonia B. G., Birkinshaw, Richard W., Liu, Ligong, Patel, Onisha, Mahony, Jennifer, Chen, Zhenjun, Reantragoon, Rangsima, Meehan, Bronwyn, Cao, Hanwei, Williamson, Nicholas A., Strugnell, Richard A., Van Sinderen, Douwe, Mak, Jeffrey Y. W., Fairlie, David P., Kjer-Nielsen, Lars, Rossjohn, Jamie and McClusky, James (2014) T-cell activation by transitory neo-antigens derived from distinct microbial pathways. Nature, 509 7500: 361-365. doi:10.1038/nature13160


Author Corbett, Alexandra J.
Eckle, Sidonia B. G.
Birkinshaw, Richard W.
Liu, Ligong
Patel, Onisha
Mahony, Jennifer
Chen, Zhenjun
Reantragoon, Rangsima
Meehan, Bronwyn
Cao, Hanwei
Williamson, Nicholas A.
Strugnell, Richard A.
Van Sinderen, Douwe
Mak, Jeffrey Y. W.
Fairlie, David P.
Kjer-Nielsen, Lars
Rossjohn, Jamie
McClusky, James
Title T-cell activation by transitory neo-antigens derived from distinct microbial pathways
Journal name Nature   Check publisher's open access policy
ISSN 0028-0836
1476-4687
Publication date 2014-04-02
Year available 2014
Sub-type Article (original research)
DOI 10.1038/nature13160
Open Access Status Not yet assessed
Volume 509
Issue 7500
Start page 361
End page 365
Total pages 5
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Abstract T cells discriminate between foreign and host molecules by recognizing distinct microbial molecules, predominantly peptides and lipids(1-4). Riboflavin precursors found in many bacteria and yeast also selectively activate mucosal-associated invariant T (MAIT) cells(5,6), an abundant population of innate-like T cells in humans(7-9). However, the genesis of these small organic molecules and their mode of presentation to MAIT cells by the major histocompatibility complex (MHC)-related protein MR1 (ref. 8) are not well understood. Here we show that MAIT-cell activation requires key genes encoding enzymes that form 5-amino-6-D-ribitylaminouracil (5-A-RU), an early intermediate in bacterial riboflavin synthesis. Although 5-A-RU does not bind MR1 or activate MAIT cells directly, it does form potent MAIT-activating antigens via non-enzymatic reactions with small molecules, such as glyoxal and methylglyoxal, which are derived from other metabolic pathways. The MAIT antigens formed by the reactions between 5-A-RU and glyoxal/methylglyoxal were simple adducts, 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil (5-OE-RU) and 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), respectively, which bound to MR1 as shown by crystal structures of MAIT TCR ternary complexes. Although 5-OP-RU and 5-OE-RU are unstable intermediates, they became trapped by MR1 as reversible covalent Schiff base complexes. Mass spectra supported the capture by MR1 of 5-OP-RU and 5-OE-RU from bacterial cultures that activate MAIT cells, but not from non-activating bacteria, indicating that these MAIT antigens are present in a range of microbes. Thus, MR1 is able to capture, stabilize and present chemically unstable pyrimidine intermediates, which otherwise convert to lumazines, as potent antigens to MAIT cells. These pyrimidine adducts are microbial signatures for MAIT-cell immunosurveillance.
Formatted abstract
T cells discriminate between foreign and host molecules by recognizing distinct microbial molecules, predominantly peptides and lipids. Riboflavin precursors found in many bacteria and yeast also selectively activate mucosal-associated invariant T (MAIT) cells, an abundant population of innate-like T cells in humans. However, the genesis of these small organic molecules and their mode of presentation to MAIT cells by the major histocompatibility complex (MHC)-related protein MR1 (ref. 8) are not well understood. Here we show that MAIT-cell activation requires key genes encoding enzymes that form 5-amino-6-d-ribitylaminouracil (5-A-RU), an early intermediate in bacterial riboflavin synthesis. Although 5-A-RU does not bind MR1 or activate MAIT cells directly, it does form potent MAIT-activating antigens via non-enzymatic reactions with small molecules, such as glyoxal and methylglyoxal, which are derived from other metabolic pathways. The MAIT antigens formed by the reactions between 5-A-RU and glyoxal/methylglyoxal were simple adducts, 5-(2-oxoethylideneamino)-6-d-ribitylaminouracil (5-OE-RU) and 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU), respectively, which bound to MR1 as shown by crystal structures of MAIT TCR ternary complexes. Although 5-OP-RU and 5-OE-RU are unstable intermediates, they became trapped by MR1 as reversible covalent Schiff base complexes. Mass spectra supported the capture by MR1 of 5-OP-RU and 5-OE-RU from bacterial cultures that activate MAIT cells, but not from non-activating bacteria, indicating that these MAIT antigens are present in a range of microbes. Thus, MR1 is able to capture, stabilize and present chemically unstable pyrimidine intermediates, which otherwise convert to lumazines, as potent antigens to MAIT cells. These pyrimidine adducts are microbial signatures for MAIT-cell immunosurveillance.
Keyword Multidisciplinary Sciences
Science & Technology - Other Topics
MULTIDISCIPLINARY SCIENCES
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 08/IN.1/B1909
1027369
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Thu, 10 Apr 2014, 21:08:10 EST by Susan Allen on behalf of Institute for Molecular Bioscience