Abstract
Mucosal associated invariant T (MAIT) cells are restricted by the monomorphic MHC class I-like molecule, MHC-related protein-1 (MR1). Until 2012, the origin of the MAIT cell antigens (Ags) was unknown, although it was established that MAIT cells could be activated by a broad range of bacteria and yeasts, possibly suggesting a conserved Ag. Using a combination of protein chemistry, mass spectrometry, cellular biology, structural biology and small molecule chemistry, we discovered MR1 ligands derived from folic acid (vitamin B9) and from an intermediate in the microbial biosynthesis of riboflavin (vitamin B2). While the folate derivative 6-formylpterin generally inhibited MAIT cell activation, two riboflavin pathway derivatives, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil and 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil, were potent MAIT cell agonists. Other intermediates and derivatives of riboflavin synthesis displayed weak or no MAIT cell activation. Collectively, these studies revealed that in addition to peptide and lipid-based Ags, small molecule natural product metabolites are also ligands that can activate T cells expressing αβ T-cell receptors, and here we recount this discovery.
| Original language | English |
|---|---|
| Pages (from-to) | 573-587 |
| Number of pages | 15 |
| Journal | Immunology and Cell Biology |
| Volume | 96 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jul 2018 |
Keywords
- 5-(2-oxoethylideneamino)-6-d-ribityl-aminouracil
- 5-(2-oxopropylidene-amino)-6-d-ribitylaminouracil
- 5-A-RU
- 5-amino-6-d-ribitylaminouracil
- 5-OE-RU
- 5-OP-RU
- Antigen
- Folic acid
- MAIT cells
- MR1
- Mucosal associated invariant T cells
- Riboflavin
- T-cell receptor
- TCR
- Vitamin B
Cite this
}
An overview on the identification of MAIT cell antigens. / Kjer-Nielsen, Lars; Corbett, Alexandra J.; Chen, Zhenjun; Liu, Ligong; Mak, Jeffrey Yw; Godfrey, Dale I.; Rossjohn, Jamie; Fairlie, David P.; Mccluskey, James; Eckle, Sidonia Bg.
In: Immunology and Cell Biology, Vol. 96, No. 6, 07.2018, p. 573-587.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - An overview on the identification of MAIT cell antigens
AU - Kjer-Nielsen, Lars
AU - Corbett, Alexandra J.
AU - Chen, Zhenjun
AU - Liu, Ligong
AU - Mak, Jeffrey Yw
AU - Godfrey, Dale I.
AU - Rossjohn, Jamie
AU - Fairlie, David P.
AU - Mccluskey, James
AU - Eckle, Sidonia Bg
PY - 2018/7
Y1 - 2018/7
N2 - Mucosal associated invariant T (MAIT) cells are restricted by the monomorphic MHC class I-like molecule, MHC-related protein-1 (MR1). Until 2012, the origin of the MAIT cell antigens (Ags) was unknown, although it was established that MAIT cells could be activated by a broad range of bacteria and yeasts, possibly suggesting a conserved Ag. Using a combination of protein chemistry, mass spectrometry, cellular biology, structural biology and small molecule chemistry, we discovered MR1 ligands derived from folic acid (vitamin B9) and from an intermediate in the microbial biosynthesis of riboflavin (vitamin B2). While the folate derivative 6-formylpterin generally inhibited MAIT cell activation, two riboflavin pathway derivatives, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil and 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil, were potent MAIT cell agonists. Other intermediates and derivatives of riboflavin synthesis displayed weak or no MAIT cell activation. Collectively, these studies revealed that in addition to peptide and lipid-based Ags, small molecule natural product metabolites are also ligands that can activate T cells expressing αβ T-cell receptors, and here we recount this discovery.
AB - Mucosal associated invariant T (MAIT) cells are restricted by the monomorphic MHC class I-like molecule, MHC-related protein-1 (MR1). Until 2012, the origin of the MAIT cell antigens (Ags) was unknown, although it was established that MAIT cells could be activated by a broad range of bacteria and yeasts, possibly suggesting a conserved Ag. Using a combination of protein chemistry, mass spectrometry, cellular biology, structural biology and small molecule chemistry, we discovered MR1 ligands derived from folic acid (vitamin B9) and from an intermediate in the microbial biosynthesis of riboflavin (vitamin B2). While the folate derivative 6-formylpterin generally inhibited MAIT cell activation, two riboflavin pathway derivatives, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil and 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil, were potent MAIT cell agonists. Other intermediates and derivatives of riboflavin synthesis displayed weak or no MAIT cell activation. Collectively, these studies revealed that in addition to peptide and lipid-based Ags, small molecule natural product metabolites are also ligands that can activate T cells expressing αβ T-cell receptors, and here we recount this discovery.
KW - 5-(2-oxoethylideneamino)-6-d-ribityl-aminouracil
KW - 5-(2-oxopropylidene-amino)-6-d-ribitylaminouracil
KW - 5-A-RU
KW - 5-amino-6-d-ribitylaminouracil
KW - 5-OE-RU
KW - 5-OP-RU
KW - Antigen
KW - Folic acid
KW - MAIT cells
KW - MR1
KW - Mucosal associated invariant T cells
KW - Riboflavin
KW - T-cell receptor
KW - TCR
KW - Vitamin B
UR - http://www.scopus.com/inward/record.url?scp=85047493425&partnerID=8YFLogxK
U2 - 10.1111/imcb.12057
DO - 10.1111/imcb.12057
M3 - Article
AN - SCOPUS:85047493425
VL - 96
SP - 573
EP - 587
JO - Immunology and Cell Biology
JF - Immunology and Cell Biology
SN - 0818-9641
IS - 6
ER -