MR1 presents microbial vitamin B metabolites to MAIT cells.
Antigen-presenting molecules, encoded by the major histocompatibility complex (MHC) and CD1 family, bind peptide- and lipid-based antigens, respectively, for recognition by T cells. Mucosal-associated invariant T (MAIT) cells are an abundant population of innate-like T cells in humans that are activated by an antigen(s) bound to the MHC class I-like molecule MR1. Although the identity of MR1-restricted antigen(s) is unknown, it is present in numerous bacteria and yeast. Here we show that the structure and chemistry within the antigen-binding cleft of MR1 is distinct from the MHC and CD1 families. MR1 is ideally suited to bind ligands originating from vitamin metabolites. The structure of MR1 in complex with 6-formyl pterin, a folic acid (vitamin B9) metabolite, shows the pterin ring sequestered within MR1. Furthermore, we characterize related MR1-restricted vitamin derivatives, originating from the bacterial riboflavin (vitamin B2) biosynthetic pathway, which specifically and potently activate MAIT cells. Accordingly, we show that metabolites of vitamin B represent a class of antigen that are presented by MR1 for MAIT-cell immunosurveillance. As many vitamin biosynthetic pathways are unique to bacteria and yeast, our data suggest that MAIT cells use these metabolites to detect microbial infection.
Department of Microbiology & Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.
Lars
L
Kjer-Nielsen
Onisha
O
Patel
Alexandra J
AJ
Corbett
Jérôme
J
Le Nours
Bronwyn
B
Meehan
Ligong
L
Liu
Mugdha
M
Bhati
Zhenjun
Z
Chen
Lyudmila
L
Kostenko
Rangsima
R
Reantragoon
Nicholas A
NA
Williamson
Anthony W
AW
Purcell
Nadine L
NL
Dudek
Malcolm J
MJ
McConville
Richard A J
RA
O'Hair
George N
GN
Khairallah
Dale I
DI
Godfrey
David P
DP
Fairlie
Jamie
J
Rossjohn
James
J
McCluskey
D017951:Antigen Presentation; D001424:Bacterial Infections / Q000276:immunology / Q000382:microbiology; D001665:Binding Sites; D002460:Cell Line; D018360:Crystallography, X-Ray; D005492:Folic Acid / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D006649:Histocompatibility Antigens / Q000737:chemistry / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007157:Immunologic Surveillance / Q000276:immunology; D019169:Jurkat Cells; D008024:Ligands; D008213:Lymphocyte Activation; D015778:Minor Histocompatibility Antigens; D008958:Models, Molecular; D058849:Protein Refolding / Q000187:drug effects; D011622:Pterins / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D012475:Salmonella / Q000276:immunology / Q000378:metabolism; D012480:Salmonella Infections / Q000276:immunology / Q000382:microbiology; D055672:Static Electricity; D013601:T-Lymphocytes / Q000276:immunology*; D001613:beta 2-Microglobulin / Q000276:immunology / Q000378:metabolism
D006649:Histocompatibility Antigens; D015395:Histocompatibility Antigens Class I; D008024:Ligands; C094840:MR1 protein, human; D015778:Minor Histocompatibility Antigens; D011622:Pterins; D001613:beta 2-Microglobulin; D005492:Folic Acid