Affinage

MR1

Major histocompatibility complex class I-related protein 1 · UniProt Q95460

Length
341 aa
Mass
39.4 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MR1 is a monomorphic, ubiquitously transcribed MHC class I-related molecule that functions as a non-peptide antigen-presenting platform, capturing small-molecule metabolites for surveillance by specialized T cell populations (PMID:9780177, PMID:12634786). Its defining ligands are intermediates of microbial riboflavin (vitamin B2) biosynthesis, with the founding crystal structure showing a folate-derived pterin sequestered within the antigen-binding cleft; riboflavin-pathway metabolites potently and specifically activate MAIT cells in an MR1-dependent manner (PMID:23051753). Subsequent unbiased mass spectrometry of MR1 immunoprecipitates established that the presented ligandome is far broader than riboflavin precursors, extending to vitamin B6 compounds (pyridoxal and pyridoxal 5-phosphate, bound via Lys43 Schiff-base formation) and endogenous carbonyl-nucleobase adducts such as the adenine adduct M3Ade, which act as self-antigens reporting cellular carbonyl stress (PMID:30006464, PMID:39589872, PMID:38728413). Antigen capture is conformationally coupled to trafficking: MR1 exists in 'open' unliganded and 'folded' ligand-bound conformers, and only the folded, ligand-stabilized form reaches the surface to activate MAIT cells (PMID:15802267, PMID:21777569). An ER-resident pool of unliganded MR1, stabilized by the chaperones tapasin and TAPBPR, supplies molecules for antigen loading; TAPBPR engages MR1 ligand-independently and catalyzes metabolite exchange within the groove (PMID:32958637, PMID:35725941). Surface dynamics are governed by AP2-dependent internalization via a cytoplasmic tyrosine motif, Rab6-dependent recycling through the trans-Golgi, and endosomal trafficking that allows ligand exchange on recycled molecules (PMID:36129434, PMID:33247182, PMID:30886396, PMID:18443227). MR1-antigen complexes are read by MAIT cell TCRs whose invariant α-chain docks centrally on MR1, with CD8 serving as a functional coreceptor, and by diverse MR1-restricted αβ and Vδ3 γδ T cells using distinct docking topologies (PMID:22412157, PMID:36018322, PMID:34845016, PMID:32817339, PMID:28518056). This sensing is regulated by TLR/NF-κB signaling, alternative splicing producing a non-functional MR1B isoform that competes with MR1A, and viral evasion via HSV-1 Us3-mediated proteasomal degradation (PMID:28518215, PMID:27105778, PMID:32963314, PMID:32130899). Functionally, MR1 sensing supports antimicrobial defense, TCR-independent MAIT-mediated wound repair through CXCR6 and amphiregulin, and tumor immunosurveillance, where tumor MR1 can paradoxically promote metastasis through MAIT cell suppression of NK function (PMID:36630919, PMID:31826876).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1998 High

    Establishing the MR1 gene structure, chromosomal location, conservation, and splicing repertoire was the foundational step defining MR1 as a candidate antigen-presenting molecule with conserved ligand-binding domains.

    Evidence cDNA cloning, genomic sequencing, Northern blot, and chromosomal mapping

    PMID:9780177

    Open questions at the time
    • No ligand or T cell partner identified at this stage
    • Functional role of secretory/alternatively spliced variants unresolved
  2. 2003 High

    Knockout of MR1 abolished MAIT cells, establishing that MR1 selects and restricts an entire innate-like T cell lineage and depends on commensal flora and B cells for their expansion.

    Evidence MR1-deficient mice and B-cell-deficient analysis with flow cytometry

    PMID:12634786

    Open questions at the time
    • Nature of the presented antigen unknown
    • Mechanism linking microbiota to MAIT expansion unresolved
  3. 2005 High

    Demonstrating that only a ligand-bound 'folded' MR1 conformer reaches the surface and activates MAIT cells established that MR1 antigen presentation is conformationally and ligand-gated, analogous to MHC-I peptide loading.

    Evidence Conformation-specific mAbs, groove mutagenesis, and MAIT hybridoma assays

    PMID:15802267

    Open questions at the time
    • Chemical identity of stabilizing ligand still unknown
    • Trafficking route not defined
  4. 2008 High

    Mapping MR1 to multivesicular endosomes and showing dependence on endosomal acidification and MHC-II chaperones, but independence from the proteasome and MHC-I loading complex, defined a distinct endocytic antigen-loading route sampling both endocytosed and endogenous antigens.

    Evidence Inhibitor and chaperone knockdown studies with subcellular fractionation and confocal localization

    PMID:18443227

    Open questions at the time
    • Molecular machinery of ER loading vs endosomal loading not separated
    • Specific chaperone interactions unidentified
  5. 2012 High

    The crystal structure of MR1 bound to a riboflavin-pathway metabolite, together with TCR structural and mutagenesis work, solved the central question of what MR1 presents and how the invariant MAIT TCR α-chain docks centrally to read it.

    Evidence Crystal structures of MR1-ligand and MAIT TCR, mutagenesis, and MAIT activation assays

    PMID:22412157 PMID:23051753

    Open questions at the time
    • Did not capture full breadth of the ligandome
    • Conformational differences between microbial and endogenous ligand presentation unresolved
  6. 2013 Medium

    Differential TCR/MR1 residue contributions in the presence versus absence of bacteria, plus biochemical resistance of the antigen to protease and lipid extraction, established that microbial and endogenous MR1 ligands are non-peptide, non-lipid and may impose distinct MR1 conformations.

    Evidence TCR and MR1 mutagenesis, proteinase K digestion, and lipid extraction with functional readouts

    PMID:23342002

    Open questions at the time
    • Endogenous ligand not chemically identified here
    • Single-lab functional inference of conformational difference
  7. 2011 Medium

    Showing that MR1 surface expression is acid-sensitive, stabilized at low temperature, and proteasome-independent reinforced that MR1 reaches the surface through ligand-dependent stabilization rather than peptide processing.

    Evidence Acid stripping, low-temperature culture, and proteasome inhibition with conformation-dependent mAbs

    PMID:21777569

    Open questions at the time
    • Identity of stabilizing ligand not determined
    • Single-lab pharmacological inference
  8. 2017 Medium

    Identification of MR1-restricted T cells recognizing self-antigens in the absence of microbes broadened MR1's role from microbial sensing to surveillance of endogenous cellular states by diverse TCRs.

    Evidence MR1 tetramer staining, T cell clone isolation, cytokine profiling, and TCR sequencing

    PMID:28518056

    Open questions at the time
    • Self-antigen chemical identity not defined at this stage
    • Single-lab clonal characterization
  9. 2016 Medium

    Dissecting how bacterial uptake into acidified endolysosomes and TLR/NF-κB signaling regulate MR1 surface expression linked innate sensing to the kinetics and magnitude of MAIT activation, including its eventual downregulation.

    Evidence Acidification inhibitors, TLR stimulation, NF-κB inhibition, and primary MAIT activation assays

    PMID:27105778

    Open questions at the time
    • Cell-type-specific differences (monocytes vs B cells) not mechanistically explained
    • Single-lab pharmacological dissection
  10. 2017 Medium

    Showing that endosomal TLR9 signaling in B cells upregulates MR1 surface expression in a manner dependent on ER-to-Golgi transport tied a specific innate receptor to MR1 trafficking and bacterial antigen presentation.

    Evidence TLR9 agonists/knockdown, transport inhibitors, and MAIT activation assays

    PMID:28518215

    Open questions at the time
    • Molecular link between TLR9 and MR1 trafficking not defined
    • Single-lab study
  11. 2018 High

    Unbiased mass spectrometry of MR1-bound microbial ligands revealed the ligandome is unexpectedly broad beyond riboflavin precursors, recognized by T cells with diverse TCRs, reframing MR1 as a presenter of chemically varied metabolites.

    Evidence Mass spectrometry of MR1 immunoprecipitates with functional T cell assays

    PMID:30006464

    Open questions at the time
    • Structural basis for accommodating diverse ligands not solved here
    • Single-lab ligandome
  12. 2019 Medium

    Distinguishing recycled MR1 ligand exchange (exogenous antigens reusing 6-FP-loaded MR1, requiring syntaxin 4) from intracellular Mtb antigen loading defined parallel, trafficking-segregated routes for MR1 antigen acquisition.

    Evidence MR1 recycling assays, syntaxin 4 knockdown, and Mtb infection with MAIT readouts

    PMID:30886396

    Open questions at the time
    • Full trafficking itinerary of each route incomplete
    • Single-lab knockdown evidence
  13. 2019 High

    Demonstrating that surface MR1 on tumor cells activates MAIT cells to suppress NK function and promote metastasis via IL17A, with blockade or deletion reducing metastasis, established a context where MR1 sensing is pro-tumorigenic.

    Evidence MR1-/- tumor models, adoptive transfer, blocking antibodies, CRISPR deletion, and cytokine neutralization

    PMID:31826876

    Open questions at the time
    • Tumor MR1 ligand identity not defined
    • Balance between pro- and anti-tumor MR1 functions unresolved
  14. 2020 High

    Defining the ER-resident unliganded MR1 pool stabilized by tapasin and TAPBPR, and a Rab6-dependent surface-recycling route, established the chaperone-supported source and trafficking circuit that supplies MR1 for metabolite presentation.

    Evidence Genome-wide CRISPR screen, chaperone knockouts, proteomics, and Rab6 manipulation with MAIT assays

    PMID:32958637 PMID:33247182

    Open questions at the time
    • Stoichiometry and handoff between ER and surface pools not resolved
    • Rab6 mechanism shown in single lab at Medium confidence
  15. 2020 High

    Showing that non-Schiff-base ligands can occupy the A'-pocket to retain MR1 in the ER and inhibit MAIT activation, and that alternative splicing yields a non-functional competing MR1B isoform, revealed ligand- and isoform-based mechanisms of negative regulation.

    Evidence In silico screening, MR1-ligand-TCR crystal structures, ER-retention imaging, isoform overexpression, and MAIT assays

    PMID:32341160 PMID:32963314

    Open questions at the time
    • Endogenous antagonist ligands not identified
    • Mechanism of MR1B competition (ligand vs chaperone) not pinned down
  16. 2020 Medium

    Identification of HSV-1 Us3-mediated proteasomal degradation of MR1, escapable by prior ligand-induced surface expression, defined an active viral evasion strategy targeting the MR1 pathway.

    Evidence Viral infection, proteasome rescue, Us3 mutant analysis, and MAIT activation assays

    PMID:32130899

    Open questions at the time
    • Molecular mechanism by which Us3 routes MR1 to degradation unresolved
    • Single-lab study
  17. 2021 High

    Crystal structures of Vδ3Vδ8 γδ TCR-MR1 complexes revealed antigen-independent recognition via contacts to the side of the groove, establishing a docking topology distinct from MAIT and other αβ TCRs.

    Evidence MR1 tetramer staining and crystal structures of γδ TCR-MR1-antigen complexes

    PMID:34845016

    Open questions at the time
    • Physiological ligand and in vivo role of γδ MR1 recognition unclear
    • Single-lab structures
  18. 2020 High

    An atypical TRAV1-2- TCR shown to bind over the MR1 F'-pocket with CDR3β contacting the 5-OP-RU antigen demonstrated that diverse MR1-restricted αβ TCRs read the same antigen through fundamentally different footprints.

    Evidence Crystal structures of the unliganded TCR and its MR1-5-OP-RU complex with functional assays

    PMID:32817339

    Open questions at the time
    • Frequency and physiological role of such atypical T cells unclear
    • Single-lab structures
  19. 2022 High

    Structural and biochemical work showed that TAPBPR engages MR1 ligand-independently and catalyzes metabolite exchange, while a cytoplasmic tyrosine motif drives AP2-dependent internalization, jointly defining how ligand exchange and surface dwell time are controlled; CD8 was shown to act as a functional coreceptor via a defined MR1 interface.

    Evidence Paramagnetic NMR and kinetics, co-IP and mutagenesis with live imaging, and MR1-CD8αα crystal structure with functional tetramers

    PMID:35725941 PMID:36018322 PMID:36129434

    Open questions at the time
    • In vivo contribution of TAPBPR catalysis to physiological loading not quantified
    • Coordination between AP2 internalization and Rab6 recycling not integrated
  20. 2023 Medium

    Demonstrating that wound-infiltrating MAIT cells promote repair through CXCR6-dependent migration and amphiregulin secretion independent of sustained TCR/MR1 stimulation established a tissue-repair function operating downstream of, but distinct from, MR1 antigen sensing.

    Evidence Skin excision models, parabiosis, adoptive transfer, CXCR6 blockade, and amphiregulin neutralization

    PMID:36630919

    Open questions at the time
    • Role of initial MR1-dependent priming in establishing repair-competent MAIT cells unclear
    • Single-lab in vivo dissection
  21. 2024 High

    Unbiased identification and structural characterization of vitamin B6 compounds and endogenous carbonyl-nucleobase adducts as bona fide MR1 ligands established that MR1 reports both nutritional metabolites and cellular carbonyl/nucleobase-metabolic stress to diverse and polyclonal MR1-reactive T cells.

    Evidence Mass spectrometry of MR1-bound metabolites, MR1-ligand crystal structures, Schiff-base assays, tetramer staining, scRNA-seq, and T cell stimulation across donor types

    PMID:38728413 PMID:39589872 PMID:39701104

    Open questions at the time
    • Relative in vivo abundance and dominance of these self-antigens not quantified
    • Therapeutic implications of carbonyl-stress sensing in cancer not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct ER-loading, endosomal-exchange, AP2-internalization, and Rab6-recycling routes are coordinated to determine which ligands are presented and for how long—and how this is reprogrammed across infection, stress, repair, and cancer—remains unresolved.
  • No unified model integrating chaperone loading, recycling, and surface dwell-time control
  • Physiological hierarchy among microbial, vitamin, and carbonyl-stress ligands undefined
  • Determinants steering MR1 toward protective versus pathological T cell responses unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 4 GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005768 endosome 3 GO:0005783 endoplasmic reticulum 3 GO:0005886 plasma membrane 3 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-9609507 Protein localization 4 R-HSA-168256 Immune System 3
Partners
AP2CD8ARAB6ASTX4TAPBPTAPBPR

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 MR1 binds and presents vitamin B2 (riboflavin) biosynthetic pathway metabolites to MAIT cells. Crystal structure of MR1 in complex with 6-formyl pterin (a folic acid metabolite) showed the pterin ring sequestered within the antigen-binding cleft of MR1. Riboflavin biosynthesis-derived metabolites specifically and potently activate MAIT cells in an MR1-dependent manner. Crystal structure determination of MR1-ligand complex, functional MAIT cell activation assays, chemical characterization of ligands Nature High 23051753
2003 MAIT cells (expressing invariant Vα7.2-Jα33 TCR in humans or Vα19-Jα33 in mice) are selected and/or restricted by MR1, as demonstrated by the absence of MAIT cells in MR1-deficient mice. Additionally, MAIT cell expansion requires B lymphocytes and commensal flora. Genetic knockout mouse model (MR1-deficient mice), flow cytometry, B-cell-deficient patient/mouse analysis Nature High 12634786
2012 The invariant MAIT TCR α-chain controls specificity for MR1 through conserved residues within the Vα-Jα regions, while the β-chain individual residues are largely dispensable. Only two centrally positioned residues of MR1's antigen-binding cleft are essential for MAIT cell activation. The MAIT TCR docks centrally on MR1, dominated by the α-chain, contrasting with the NKT TCR-CD1d interaction. Crystal structure of human MAIT TCR, site-directed mutagenesis of MAIT TCR and MR1 residues, functional MAIT cell activation assays The Journal of experimental medicine High 22412157
2005 MR1 has an antigen presentation function that is ligand-dependent. MR1 molecules exist in 'open' (unloaded) or 'folded' (ligand-bound) conformations analogous to MHC class I peptide-induced conformational changes; only the folded conformer activates MAIT cells. Mutations in the putative ligand-binding groove abolish surface expression of folded MR1 or disrupt MAIT cell activation. Monoclonal antibody generation in MR1 KO mice, site-directed mutagenesis of MR1 groove residues, MAIT hybridoma activation assays, surface expression analysis The Journal of biological chemistry High 15802267
2008 MR1 uses an endocytic pathway for antigen presentation to MAIT cells. MR1 localizes in multivesicular endosomes; MAIT cell activation is independent of proteasome processing and MHC class I peptide loading complex, but is enhanced by MHC class II chaperones Ii and DM, is reduced when endogenous Ii is silenced, and is abolished by inhibition of endosomal acidification. These findings demonstrate MR1 traffics through endocytic compartments to sample both endocytosed and endogenous antigens. Inhibitor studies (proteasome inhibitors, acidification inhibitors), chaperone overexpression/siRNA knockdown, subcellular fractionation, confocal localization of MR1 in multivesicular endosomes, MAIT cell activation assays The Journal of experimental medicine High 18443227
1998 MR1 is encoded at human chromosome 1q25.3 and generates multiple transcripts via alternative splicing, including secretory variants lacking the Ig-like α3 domain. MR1 is ubiquitously transcribed across cell lineages. The murine orthologue maps to a syntenic segment of chromosome 1. The α1/α2 domains (putative ligand-binding) show ~90% amino acid identity between human and mouse. cDNA cloning, genomic sequencing (18,769 bp locus), Northern blot, RACE, alternative splicing characterization, chromosomal mapping Journal of immunology High 9780177
2017 MR1 can present non-microbial, cell-derived (self) antigens to a population of MR1-restricted T cells (MR1T cells) with diverse TCRs, distinct from MAIT cells. These MR1T cells recognize MR1-expressing cells in the absence of microbial ligands, display functional heterogeneity, and exhibit T helper-like capacities upon MR1-dependent recognition. MR1 tetramer staining, T cell clone isolation and functional analysis, cytokine profiling, TCR sequencing eLife Medium 28518056
2018 Mass spectrometry analysis of MR1-bound ligands from E. coli and M. smegmatis revealed that the MR1 ligandome is unexpectedly broad, containing functionally distinct ligands beyond riboflavin precursors, which are recognized by MR1-restricted T cells with diverse TCR usage. Mass spectrometry-based ligandome analysis of MR1 immunoprecipitates from microbe-exposed cells, functional T cell activation assays with identified ligands Science immunology High 30006464
2020 Ligand-dependent downregulation of MR1 cell surface expression: two compounds (DB28 and NV18.1) identified via in silico screening bind within the A'-pocket of MR1 without forming a Schiff base, retain MR1 in the ER in an immature form, compete with stimulatory MR1 ligands, and inhibit MAIT cell activation. Crystal structures of MAIT TCR complexed with MR1-DB28 and MR1-NV18.1 revealed both ligands in the A'-pocket, sequestered by hydrophobic and polar contacts. In silico ligand screening, crystal structures of MR1-ligand-TCR complexes, confocal microscopy for ER retention, MAIT cell activation assays Proceedings of the National Academy of Sciences High 32341160
2020 The ER contains a pool of unliganded MR1 in two conformers stabilized via interactions with chaperones tapasin and tapasin-related protein (TAPBPR). This ER-resident pool is the primary source of MR1 molecules for presentation of exogenous metabolite antigens to MAIT cells. Deletion of these chaperones reduces the ER-resident MR1 pool and hampers antigen presentation and MAIT cell activation. Fluorophore-labeled stable MR1 antigen analog, conformation-specific MR1 mAb, proteomic analysis, genome-wide CRISPR/Cas9 library screen, chaperone knockout validation Proceedings of the National Academy of Sciences High 32958637
2020 HSV-1 inhibits MR1 cell surface upregulation and targets MR1 for proteasomal degradation via the Us3 viral gene product. Ligand-induced MR1 surface expression prior to infection allows MR1 to escape HSV-1-dependent targeting. HSV-1 downregulation of MR1 disrupts MAIT TCR activation. Viral infection experiments, proteasome inhibitor rescue, Us3 viral gene identification via mutant virus analysis, flow cytometry for MR1 surface expression, MAIT cell activation assays Cell reports Medium 32130899
2022 TAPBPR recognizes MR1 in a ligand-independent manner (unlike MHC-I), owing to the absence of major structural changes in the MR1 α2-1 helix between empty and ligand-loaded states. TAPBPR engages conserved surfaces on MR1 and can affect the exchange kinetics of noncovalent metabolites within the MR1 groove, acting as a catalyst for ligand exchange. In vitro biochemical assays, paramagnetic NMR with restrained molecular dynamics simulations, 19F-labeled diclofenac NMR relaxation dispersion experiments Nature chemical biology High 35725941
2022 Human MR1 contains a tyrosine-based motif in its cytoplasmic domain that mediates low-affinity binding with the endocytic adaptor protein 2 (AP2) complex. This interaction controls the kinetics of MR1 internalization from the cell surface and minimizes recycling, defining the duration of antigen presentation to MAIT cells. Co-immunoprecipitation of MR1 cytoplasmic domain with AP2, mutational analysis of tyrosine-based motif, live cell imaging of MR1 internalization kinetics, MAIT cell activation assays The Journal of cell biology High 36129434
2020 Rab6, a small GTPase, regulates recycling of MR1 molecules from the cell surface through endosomal compartments to the trans-Golgi network (TGN). This Rab6-dependent recycled pool of MR1 is available for reloading with ligands from bacterial pathogens like M. tuberculosis and is important for MAIT cell recognition of infected cells. Inducible MR1 expression system, Rab6 knockdown/dominant-negative experiments, endosomal trafficking inhibitors, MAIT cell activation assays Scientific reports Medium 33247182
2019 MR1-dependent antigen presentation can be distinguished between intracellular M. tuberculosis infection and exogenously added antigens: only exogenously added antigens can reuse MR1 previously bound to the folic acid metabolite 6-FP (ligand exchange/recycling). Syntaxin 4 (an endosomal trafficking protein) is specifically involved in presentation of exogenously delivered antigens but not Mtb-derived antigen presentation. MR1 recycling assays using 6-FP-loaded MR1, Syntaxin 4 knockdown, M. tuberculosis infection experiments, MAIT cell activation assays Scientific reports Medium 30886396
2020 Alternative splicing of MR1 regulates antigen presentation: the full-length isoform MR1A can activate MAIT cells, while MR1B cannot. Coexpression of MR1B with MR1A decreases MAIT cell activation following bacterial infection, and MR1B expression prior to MR1A lowers total MR1A abundance, suggesting competition between isoforms for ligands or chaperones required for folding/trafficking. Transcriptomic analysis, qPCR, overexpression of individual MR1 isoforms, bacterial infection experiments, MAIT cell activation assays Scientific reports Medium 32963314
2017 TLR9 signaling in B cells regulates MR1 surface expression and MR1-mediated bacterial antigen presentation. CpG-A (but not CpG-B) activates early endosomal TLR9 in B cells to increase MR1 surface expression; TLR9 knockdown reduces MR1 surface expression and antigen presentation. Blocking ER-to-Golgi transport (but not lysosomal acidification) suppresses MR1 antigen presentation in B cells. TLR agonist treatment, shRNA knockdown of TLR9, inhibitors of ER-to-Golgi transport vs. lysosomal acidification, flow cytometry for MR1 surface expression, MAIT cell activation assays Immunology Medium 28518215
2016 Uptake of intact bacteria by antigen presenting cells into acidified endolysosomal compartments is required for efficient MR1-mediated MAIT cell activation. TLR signaling increases MR1 surface expression on monocytic THP-1 but not B-cell lines, and NF-κB signaling is critical for MR1-mediated MAIT cell activation. Prolonged TLR signaling leads to downregulation of MR1-mediated MAIT cell activation. Endolysosomal acidification inhibitors, TLR ligand stimulation, NF-κB inhibition, flow cytometry for MR1 surface expression, primary human MAIT cell activation assays European journal of immunology Medium 27105778
2022 CD8 engages MR1 analogously to how it engages classical MHC-I molecules. Crystal structure of MR1-CD8αα revealed the binding interface. CD8αα and CD8αβ both enhanced MR1 binding and cytokine production by MAIT cells. The CD8-MR1 interaction was critical for recognition of folate-derived antigens by other MR1-reactive T cells. Crystal structure of MR1-CD8αα complex, MR1 tetramers mutated at the CD8 binding site, cytokine production assays, T cell functional assays The Journal of experimental medicine High 36018322
2021 Vδ3Vγ8 γδ T cells recognize MR1 in an antigen-independent manner. Crystal structures of two Vδ3Vγ8 TCR-MR1-antigen complexes revealed that the Vδ3 chain mediates specific contacts to the side of the MR1 antigen-binding groove without contacting the presented antigen, representing a previously uncharacterized MR1 docking topology distinct from MAIT TCR and other αβ TCR docking modes. MR1 tetramer staining, crystal structures of Vδ3Vγ8 TCR-MR1-antigen complexes, functional T cell characterization Proceedings of the National Academy of Sciences High 34845016
2020 Atypical TRAV1-2- TCR (D462-E4, using TRAV12-2/TRBV29-1) recognizes MR1-antigen complexes with a distinct docking topology: the TRBV29-1 β-chain binds over the F'-pocket of MR1, with CDR3β projecting into the F'-pocket and making direct contact with the 5-OP-RU antigen, contrasting with canonical MAIT TCR and TRAV36+ TCR footprints on MR1. Crystal structures of unliganded D462-E4 TCR and its complex with MR1-5-OP-RU, functional T cell assays The Journal of biological chemistry High 32817339
2011 MR1 cell surface expression is acid-sensitive (lost at pH 3.3, similar to classical MHC-I), enhanced upon culture at 26°C (consistent with ligand-dependent stabilization), and its re-expression after acid stripping is independent of proteasome activity, indicating MR1 requires proteasome-independent ligands to reach the cell surface. Acid stripping of cell surface MR1, proteasome inhibitor treatment, low-temperature culture (26°C), flow cytometry with conformation-dependent mAbs Biochemical and biophysical research communications Medium 21777569
2013 Mutational analysis of both MAIT TCR and MR1 revealed differential contribution of specific amino acids to the MAIT TCR-MR1 interaction depending on whether bacteria are present, supporting the hypothesis that the MR1 conformation/structure differs when presenting microbial-derived ligand versus endogenous ligand. The microbial-derived ligand is resistant to proteinase K digestion and does not extract with common lipids, suggesting a non-lipid, non-peptide antigen class. Site-directed mutagenesis of MAIT TCR and MR1, MAIT cell activation assays with bacterially infected or uninfected APCs, proteinase K digestion, lipid extraction PloS one Medium 23342002
2024 Pyridoxal (vitamin B6) and pyridoxal 5-phosphate are naturally presented MR1 ligands identified by unbiased mass spectrometry of MR1-bound metabolites. These compounds bind to MR1 via Lys43-mediated Schiff-base formation and enable cell surface upregulation of MR1. Crystal structures of MR1 in complex with pyridoxal and pyridoxal 5-phosphate show how these ligands are accommodated within the A-pocket of MR1. T cells transduced with the 7.G5 'pan-cancer' TCR are specifically activated by pyridoxal presented by MR1-expressing APCs. Unbiased mass spectrometry of MR1-bound metabolites, crystal structures of MR1-pyridoxal and MR1-pyridoxal 5-phosphate complexes, Schiff-base formation assays, MR1 surface upregulation assays, T cell activation with anti-MR1 antibody blocking Proceedings of the National Academy of Sciences High 39589872
2024 Carbonyl adducts of nucleobases (e.g., M3Ade — a carbonyl adduct of adenine) are sequestered in the A' pocket of MR1 and act as self-antigens stimulating MR1T cells. Carbonyl stress and changes in nucleobase metabolism in target cells promote MR1T cell activation. Drugs that induce carbonyl accumulation enhance the abundance and antigenicity of these carbonyl-nucleobase adducts within MR1. Genetic, pharmacological, and biochemical approaches; mass spectrometry detection of carbonyl-nucleobase adducts in MR1; MR1-M3Ade tetramer staining; T cell clone stimulation assays; ex vivo identification of MR1-reactive T cells Science immunology High 38728413
2024 M3Ade (a cell-endogenous carbonyl adduct of adenine) is sequestered in the A' pocket of MR1 and stimulates a heterogeneous, polyclonal population of MR1-reactive T cells ex vivo. MR1-M3Ade tetramers identified MR1-reactive T cells with phenotypic, transcriptional, and functional diversity in healthy donors, AML patients, and tumor-infiltrating lymphocytes. Mass spectrometry identification of M3Ade in MR1, MR1-M3Ade tetramer construction and staining, T cell clone stimulation, single-cell RNA sequencing, TCR repertoire analysis Immunity High 39701104
2023 Following skin excision, MAIT cells migrate into the wound in a TCR-independent but CXCR6 chemokine receptor-dependent manner. MAIT cells secrete amphiregulin upon excision, which promotes wound healing and keratinocyte proliferation. The repair function operates independently of sustained TCR/MR1 stimulation. Skin graft experiments, parabiosis, adoptive transfer, CXCR6 blocking, amphiregulin neutralization, skin excision mouse model, single-cell RNA sequencing Immunity Medium 36630919
2019 Tumor cells express MR1 on their surface following MR1 ligand exposure. MR1-expressing tumor cells activate MAIT cells to suppress NK cell effector function, promoting tumor metastasis partly via IL17A. MR1-blocking antibodies decreased lung metastases and suppressed tumor growth. MR1 deletion from tumor cells resulted in fewer metastases. MR1-/- mouse tumor models, adoptive transfer of MAIT cells into MR1-/- mice, MR1-blocking antibody treatment, CRISPR MR1 deletion in tumor cell lines, NK cell depletion experiments, IL17A neutralization Cancer discovery High 31826876

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 1098 23051753
2003 Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 933 12634786
2013 Antigen-loaded MR1 tetramers define T cell receptor heterogeneity in mucosal-associated invariant T cells. The Journal of experimental medicine 503 24101382
2018 Human blood MAIT cell subsets defined using MR1 tetramers. Immunology and cell biology 217 29437263
2014 MR1-restricted MAIT cells display ligand discrimination and pathogen selectivity through distinct T cell receptor usage. The Journal of experimental medicine 173 25049333
1998 Genomics, isoforms, expression, and phylogeny of the MHC class I-related MR1 gene. Journal of immunology (Baltimore, Md. : 1950) 167 9780177
2012 Structural insight into MR1-mediated recognition of the mucosal associated invariant T cell receptor. The Journal of experimental medicine 162 22412157
2005 Global transcriptome analysis of Shewanella oneidensis MR-1 exposed to different terminal electron acceptors. Journal of bacteriology 161 16199584
2017 Functionally diverse human T cells recognize non-microbial antigens presented by MR1. eLife 157 28518056
2010 Phage-induced lysis enhances biofilm formation in Shewanella oneidensis MR-1. The ISME journal 147 20962878
2016 The Immunology of CD1- and MR1-Restricted T Cells. Annual review of immunology 139 26927205
2005 Evidence for MR1 antigen presentation to mucosal-associated invariant T cells. The Journal of biological chemistry 139 15802267
2018 Ultrastructure of Shewanella oneidensis MR-1 nanowires revealed by electron cryotomography. Proceedings of the National Academy of Sciences of the United States of America 133 29555764
2018 MR1 displays the microbial metabolome driving selective MR1-restricted T cell receptor usage. Science immunology 127 30006464
2019 MAIT Cells Promote Tumor Initiation, Growth, and Metastases via Tumor MR1. Cancer discovery 124 31826876
2008 MR1 uses an endocytic pathway to activate mucosal-associated invariant T cells. The Journal of experimental medicine 122 18443227
2015 Lipid and small-molecule display by CD1 and MR1. Nature reviews. Immunology 121 26388332
2007 Characterization of protein-protein interactions involved in iron reduction by Shewanella oneidensis MR-1. Applied and environmental microbiology 115 17675441
2015 High expression of CD26 accurately identifies human bacteria-reactive MR1-restricted MAIT cells. Immunology 113 25752900
2006 CD1d- and MR1-restricted invariant T cells: of mice and men. Current opinion in immunology 110 16870416
2018 Tuning of human MAIT cell activation by commensal bacteria species and MR1-dependent T-cell presentation. Mucosal immunology 103 30115998
2016 TLR signaling in human antigen-presenting cells regulates MR1-dependent activation of MAIT cells. European journal of immunology 103 27105778
2016 MR1-restricted mucosal-associated invariant T (MAIT) cells respond to mycobacterial vaccination and infection in nonhuman primates. Mucosal immunology 88 27759023
2019 Diverse MR1-restricted T cells in mice and humans. Nature communications 83 31113973
2008 Probing regulon of ArcA in Shewanella oneidensis MR-1 by integrated genomic analyses. BMC genomics 83 18221523
2006 Hydrogen metabolism in Shewanella oneidensis MR-1. Applied and environmental microbiology 82 17189435
2015 MR1-restricted mucosal associated invariant T (MAIT) cells in the immune response to Mycobacterium tuberculosis. Immunological reviews 81 25703558
2012 Exceptionally high conservation of the MHC class I-related gene, MR1, among mammals. Immunogenetics 80 23229473
2012 Co-dependents: MR1-restricted MAIT cells and their antimicrobial function. Nature reviews. Microbiology 79 23178389
2023 Role of MR1-driven signals and amphiregulin on the recruitment and repair function of MAIT cells during skin wound healing. Immunity 76 36630919
2020 Ligand-dependent downregulation of MR1 cell surface expression. Proceedings of the National Academy of Sciences of the United States of America 67 32341160
2013 MAITs, MR1 and vitamin B metabolites. Current opinion in immunology 65 24556396
2016 A polymorphism in human MR1 is associated with mRNA expression and susceptibility to tuberculosis. Genes and immunity 63 27881839
2017 MAIT cells and MR1-antigen recognition. Current opinion in immunology 62 28494326
2021 Recognition of the antigen-presenting molecule MR1 by a Vδ3+ γδ T cell receptor. Proceedings of the National Academy of Sciences of the United States of America 59 34845016
2020 Endoplasmic reticulum chaperones stabilize ligand-receptive MR1 molecules for efficient presentation of metabolite antigens. Proceedings of the National Academy of Sciences of the United States of America 56 32958637
2019 MR1-Independent Activation of Human Mucosal-Associated Invariant T Cells by Mycobacteria. Journal of immunology (Baltimore, Md. : 1950) 56 31611259
2020 Human liver CD8+ MAIT cells exert TCR/MR1-independent innate-like cytotoxicity in response to IL-15. Journal of hepatology 55 32247824
2021 Shewanella oneidensis MR-1 as a bacterial platform for electro-biotechnology. Essays in biochemistry 51 33769488
2015 Catabolic and regulatory systems in Shewanella oneidensis MR-1 involved in electricity generation in microbial fuel cells. Frontiers in microbiology 50 26136738
2023 MR1 antigen presentation to MAIT cells and other MR1-restricted T cells. Nature reviews. Immunology 49 37773272
2020 Virus-Mediated Suppression of the Antigen Presentation Molecule MR1. Cell reports 48 32130899
2016 MAIT, MR1, microbes and riboflavin: a paradigm for the co-evolution of invariant TCRs and restricting MHCI-like molecules? Immunogenetics 47 27393664
2019 A Synthetic Plasmid Toolkit for Shewanella oneidensis MR-1. Frontiers in microbiology 46 30906287
2015 MR1 presentation of vitamin B-based metabolite ligands. Current opinion in immunology 46 25603223
2010 Conservation of mucosal associated invariant T (MAIT) cells and the MR1 restriction element in ruminants, and abundance of MAIT cells in spleen. Veterinary research 46 20507818
2022 CD8 coreceptor engagement of MR1 enhances antigen responsiveness by human MAIT and other MR1-reactive T cells. The Journal of experimental medicine 40 36018322
2018 The Diverse Family of MR1-Restricted T Cells. Journal of immunology (Baltimore, Md. : 1950) 38 30397170
2017 Expression and trafficking of MR1. Immunology 38 28419492
2013 MAIT cell recognition of MR1 on bacterially infected and uninfected cells. PloS one 38 23342002
2020 Antigen Recognition by MR1-Reactive T Cells; MAIT Cells, Metabolites, and Remaining Mysteries. Frontiers in immunology 37 32973800
2024 Nucleobase adducts bind MR1 and stimulate MR1-restricted T cells. Science immunology 33 38728413
2011 Energy-dependent stability of Shewanella oneidensis MR-1 biofilms. Journal of bacteriology 33 21572002
2018 Synthesis, stabilization, and characterization of the MR1 ligand precursor 5-amino-6-D-ribitylaminouracil (5-A-RU). PloS one 32 29401462
2017 How MR1 Presents a Pathogen Metabolic Signature to Mucosal-Associated Invariant T (MAIT) Cells. Trends in immunology 32 28688841
2015 CD1d- and MR1-Restricted T Cells in Sepsis. Frontiers in immunology 32 26322041
2019 MR1 recycling and blockade of endosomal trafficking reveal distinguishable antigen presentation pathways between Mycobacterium tuberculosis infection and exogenously delivered antigens. Scientific reports 31 30886396
2004 Characterization of MR-1, a novel myofibrillogenesis regulator in human muscle. Acta biochimica et biophysica Sinica 31 15188056
2021 The burgeoning role of MR1-restricted T-cells in infection, cancer and autoimmune disease. Current opinion in immunology 30 33434741
2020 MR1-Restricted T Cells Are Unprecedented Cancer Fighters. Frontiers in immunology 29 32411144
2018 Role of CD1d- and MR1-Restricted T Cells in Asthma. Frontiers in immunology 29 30210497
2019 Microbiota of MR1 deficient mice confer resistance against Clostridium difficile infection. PloS one 27 31560732
2017 The Toll-like receptor 9 signalling pathway regulates MR1-mediated bacterial antigen presentation in B cells. Immunology 26 28518215
2023 Promiscuous recognition of MR1 drives self-reactive mucosal-associated invariant T cell responses. The Journal of experimental medicine 24 37382893
2022 Mechanism of Action and Structure-Activity Relationship of α-Conotoxin Mr1.1 at the Human α9α10 Nicotinic Acetylcholine Receptor. Journal of medicinal chemistry 24 36137181
2018 Mucosal-associated invariant T cell receptor recognition of small molecules presented by MR1. Immunology and cell biology 24 29393543
2016 Engineering of Isogenic Cells Deficient for MR1 with a CRISPR/Cas9 Lentiviral System: Tools To Study Microbial Antigen Processing and Presentation to Human MR1-Restricted T Cells. Journal of immunology (Baltimore, Md. : 1950) 24 27307560
2016 Effective methods for extracting extracellular polymeric substances from Shewanella oneidensis MR-1. Water science and technology : a journal of the International Association on Water Pollution Research 24 27997408
2012 Functional specificity of extracellular nucleases of Shewanella oneidensis MR-1. Applied and environmental microbiology 24 22492434
1998 Isolation and molecular characterization of the rat MR1 homologue, a non-MHC-linked class I-related gene. Immunogenetics 24 9553154
2016 Mammalian CD1 and MR1 genes. Immunogenetics 23 27470004
2024 MR1 presents vitamin B6-related compounds for recognition by MR1-reactive T cells. Proceedings of the National Academy of Sciences of the United States of America 22 39589872
2018 MR1 antigen presentation to MAIT cells: new ligands, diverse pathways? Current opinion in immunology 22 29754112
2018 MR1-dependent antigen presentation. Seminars in cell & developmental biology 22 30449535
2000 A study on the polymorphism of human MHC class I-related MR1 gene and identification of an MR1-like pseudogene. Tissue antigens 22 11019920
2022 The roles of DmsEFAB and MtrCAB in extracellular reduction of iodate by Shewanella oneidensis MR-1 with lactate as the sole electron donor. Environmental microbiology 21 35837844
2022 A specialized tyrosine-based endocytosis signal in MR1 controls antigen presentation to MAIT cells. The Journal of cell biology 20 36129434
2021 MR1 encompasses at least six allele groups with coding region alterations. HLA 20 34351076
2019 Capturing the antigen landscape: HLA-E, CD1 and MR1. Current opinion in immunology 20 31445404
2011 Human MR1 expression on the cell surface is acid sensitive, proteasome independent and increases after culturing at 26°C. Biochemical and biophysical research communications 20 21777569
2020 Atypical TRAV1-2- T cell receptor recognition of the antigen-presenting molecule MR1. The Journal of biological chemistry 19 32817339
2016 Mutation Analysis of MR-1, SLC2A1, and CLCN1 in 28 PRRT2-negative Paroxysmal Kinesigenic Dyskinesia Patients. Chinese medical journal 19 27098784
2023 Control of the temporal development of Alzheimer's disease pathology by the MR1/MAIT cell axis. Journal of neuroinflammation 18 36944969
2022 TAPBPR employs a ligand-independent docking mechanism to chaperone MR1 molecules. Nature chemical biology 18 35725941
2020 Alternative splicing of MR1 regulates antigen presentation to MAIT cells. Scientific reports 18 32963314
2025 Cigarette smoke components modulate the MR1-MAIT axis. The Journal of experimental medicine 17 39820322
2024 The carbonyl nucleobase adduct M3Ade is a potent antigen for adaptive polyclonal MR1-restricted T cells. Immunity 17 39701104
2023 Targeting the MR1-MAIT cell axis improves vaccine efficacy and affords protection against viral pathogens. PLoS pathogens 17 37384813
2020 Covering All the Bases: Complementary MR1 Antigen Presentation Pathways Sample Diverse Antigens and Intracellular Compartments. Frontiers in immunology 17 32983150
2020 Rab6 regulates recycling and retrograde trafficking of MR1 molecules. Scientific reports 17 33247182
2024 Delivery of loaded MR1 monomer results in efficient ligand exchange to host MR1 and subsequent MR1T cell activation. Communications biology 16 38402309
2015 Adoptive T Cell Therapy Targeting CD1 and MR1. Frontiers in immunology 16 26052329
2014 Human T cells use CD1 and MR1 to recognize lipids and small molecules. Current opinion in chemical biology 16 25271021
2020 Brain astrocytes and microglia express functional MR1 molecules that present microbial antigens to mucosal-associated invariant T (MAIT) cells. Journal of neuroimmunology 15 33096293
2024 MR1-restricted T cell clonotypes are associated with "resistance" to Mycobacterium tuberculosis infection. JCI insight 14 38716731
2023 Soluble Iron Enhances Extracellular Electron Uptake by Shewanella oneidensis MR-1. ChemElectroChem 14 37649707
2022 NADH dehydrogenases drive inward electron transfer in Shewanella oneidensis MR-1. Microbial biotechnology 14 36420671
2020 MR1: a multi-faceted metabolite sensor for T cell activation. Current opinion in immunology 14 32604057
2019 The effect of MR1 ligand glyco-analogues on mucosal-associated invariant T (MAIT) cell activation. Organic & biomolecular chemistry 14 31497838
2017 CRP Regulates D-Lactate Oxidation in Shewanella oneidensis MR-1. Frontiers in microbiology 14 28559887

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