Abstract
The major-histocompatibility-complex-(MHC)-class-I-related molecule MR1 can present activating and non-activating vitamin-B-based ligands to mucosal-associated invariant T cells (MAIT cells). Whether MR1 binds other ligands is unknown. Here we identified a range of small organic molecules, drugs, drug metabolites and drug-like molecules, including salicylates and diclofenac, as MR1-binding ligands. Some of these ligands inhibited MAIT cells ex vivo and in vivo, while others, including diclofenac metabolites, were agonists. Crystal structures of a T cell antigen receptor (TCR) from a MAIT cell in complex with MR1 bound to the non-stimulatory and stimulatory compounds showed distinct ligand orientations and contacts within MR1, which highlighted the versatility of the MR1 binding pocket. The findings demonstrated that MR1 was able to capture chemically diverse structures, spanning mono- and bicyclic compounds, that either inhibited or activated MAIT cells. This indicated that drugs and drug-like molecules can modulate MAIT cell function in mammals.
| Original language | English |
|---|---|
| Pages (from-to) | 402-411 |
| Number of pages | 14 |
| Journal | Nature Immunology |
| Volume | 18 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 2017 |
Keywords
- antigen processing and presentation
- innate immune cells
Cite this
}
Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells. / Keller, Andrew n; Eckle, Sidonia B G; Xu, Weijun; Liu, Ligong; Hughes, Victoria A; Mak, Jeffrey Y W; Meehan, Bronwyn S; Pediongco, Troi; Birkinshaw, Richard W; Chen, Zhenjun; Wang, Huimeng; D'Souza, Criselle; Kjer-Nielsen, Lars; Gherardin, Nicholas A; Godfrey, Dale I; Kostenko, Lyudmila; Corbett, Alexandra J; Purcell, Anthony W; Fairlie, David P; McCluskey, James; Rossjohn, Jamie.
In: Nature Immunology, Vol. 18, No. 4, 04.2017, p. 402-411.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells
AU - Keller, Andrew n
AU - Eckle, Sidonia B G
AU - Xu, Weijun
AU - Liu, Ligong
AU - Hughes, Victoria A
AU - Mak, Jeffrey Y W
AU - Meehan, Bronwyn S
AU - Pediongco, Troi
AU - Birkinshaw, Richard W
AU - Chen, Zhenjun
AU - Wang, Huimeng
AU - D'Souza, Criselle
AU - Kjer-Nielsen, Lars
AU - Gherardin, Nicholas A
AU - Godfrey, Dale I
AU - Kostenko, Lyudmila
AU - Corbett, Alexandra J
AU - Purcell, Anthony W
AU - Fairlie, David P
AU - McCluskey, James
AU - Rossjohn, Jamie
PY - 2017/4
Y1 - 2017/4
N2 - The major-histocompatibility-complex-(MHC)-class-I-related molecule MR1 can present activating and non-activating vitamin-B-based ligands to mucosal-associated invariant T cells (MAIT cells). Whether MR1 binds other ligands is unknown. Here we identified a range of small organic molecules, drugs, drug metabolites and drug-like molecules, including salicylates and diclofenac, as MR1-binding ligands. Some of these ligands inhibited MAIT cells ex vivo and in vivo, while others, including diclofenac metabolites, were agonists. Crystal structures of a T cell antigen receptor (TCR) from a MAIT cell in complex with MR1 bound to the non-stimulatory and stimulatory compounds showed distinct ligand orientations and contacts within MR1, which highlighted the versatility of the MR1 binding pocket. The findings demonstrated that MR1 was able to capture chemically diverse structures, spanning mono- and bicyclic compounds, that either inhibited or activated MAIT cells. This indicated that drugs and drug-like molecules can modulate MAIT cell function in mammals.
AB - The major-histocompatibility-complex-(MHC)-class-I-related molecule MR1 can present activating and non-activating vitamin-B-based ligands to mucosal-associated invariant T cells (MAIT cells). Whether MR1 binds other ligands is unknown. Here we identified a range of small organic molecules, drugs, drug metabolites and drug-like molecules, including salicylates and diclofenac, as MR1-binding ligands. Some of these ligands inhibited MAIT cells ex vivo and in vivo, while others, including diclofenac metabolites, were agonists. Crystal structures of a T cell antigen receptor (TCR) from a MAIT cell in complex with MR1 bound to the non-stimulatory and stimulatory compounds showed distinct ligand orientations and contacts within MR1, which highlighted the versatility of the MR1 binding pocket. The findings demonstrated that MR1 was able to capture chemically diverse structures, spanning mono- and bicyclic compounds, that either inhibited or activated MAIT cells. This indicated that drugs and drug-like molecules can modulate MAIT cell function in mammals.
KW - antigen processing and presentation
KW - innate immune cells
UR - http://www.scopus.com/inward/record.url?scp=85011659580&partnerID=8YFLogxK
U2 - 10.1038/ni.3679
DO - 10.1038/ni.3679
M3 - Article
VL - 18
SP - 402
EP - 411
JO - Nature Immunology
JF - Nature Immunology
SN - 1529-2908
IS - 4
ER -