ORCID Profile
0000-0002-2221-7636
Current Organisation
Monash University
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Cellular Immunology | Biochemistry and Cell Biology | Structural Biology (incl. Macromolecular Modelling) | Immunology not elsewhere classified | Immunology | Evolutionary Biology not elsewhere classified |
Expanding Knowledge in the Biological Sciences | Health not elsewhere classified | Immune System and Allergy
Publisher: Proceedings of the National Academy of Sciences
Date: 19-01-2018
Abstract: MHC class I-like CD1 molecules have evolved to present lipid-based antigens to T cells. Differences in the antigen-binding clefts of the CD1 family members determine the conformation and size of the lipids that are presented, although the factors that shape CD1 ersity remain unclear. In mice, two homologous genes, CD1D1 and CD1D2, encode the CD1d protein, which is essential to the development and function of natural killer T (NKT) cells. However, it remains unclear whether both CD1d isoforms are equivalent in their antigen presentation capacity and functions. Here, we report that CD1d2 molecules are expressed in the thymus of some mouse strains, where they select functional type I NKT cells. Intriguingly, the T cell antigen receptor repertoire and phenotype of CD1d2-selected type I NKT cells in CD1D1 −/− mice differed from CD1d1-selected type I NKT cells. The structures of CD1d2 in complex with endogenous lipids and a truncated acyl-chain analog of α-galactosylceramide revealed that its A′-pocket was restricted in size compared with CD1d1. Accordingly, CD1d2 molecules could not present glycolipid antigens with long acyl chains efficiently, favoring the presentation of short acyl chain antigens. These results indicate that the two CD1d molecules present different sets of self-antigen(s) in the mouse thymus, thereby impacting the development of invariant NKT cells.
Publisher: Elsevier BV
Date: 07-2018
Publisher: Springer Science and Business Media LLC
Date: 27-10-2016
DOI: 10.1038/NCOMMS13257
Abstract: CD1 proteins present microbial lipids to T cells. Germline-encoded mycolyl lipid-reactive (GEM) T cells with conserved αβ T cell receptors (TCRs) recognize CD1b presenting mycobacterial mycolates. As the molecular basis underpinning TCR recognition of CD1b remains unknown, here we determine the structure of a GEM TCR bound to CD1b presenting glucose-6- O -monomycolate (GMM). The GEM TCR docks centrally above CD1b, whereby the conserved TCR α-chain extensively contacts CD1b and GMM. Through mutagenesis and study of T cells from tuberculosis patients, we identify a consensus CD1b footprint of TCRs present among GEM T cells. Using both the TCR α- and β-chains as tweezers to surround and grip the glucose moiety of GMM, GEM TCRs create a highly specific mechanism for recognizing this mycobacterial glycolipid.
Publisher: Elsevier BV
Date: 07-2010
Publisher: Elsevier BV
Date: 07-2004
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.JMB.2010.02.021
Abstract: Aldo-keto reductases (AKRs) are a large superfamily of NADPH-dependent enzymes that catalyze the reduction of aldehydes, aldoses, dicarbonyls, steroids, and monosaccharides. While their precise physiological role is generally unknown, AKRs are nevertheless involved in the detoxification of a broad range of toxic metabolites. Mycobacteria contain a number of AKRs, the majority of which are uncharacterised. Here, we report the 1.9 and 1.6 A resolution structures of the apoenzyme and NADPH-bound forms, respectively, of an AKR (MSMEG_2407) from Mycobacterium smegmatis, a close homologue of the M. tuberculosis enzyme Rv2971, whose function is essential to this bacterium. MSMEG_2407 adopted the triosephosphate isomerase (alpha/beta)(8)-barrel fold exhibited by other AKRs. MSMEG_2407 (AKR5H1) bound NADPH via an induced-fit mechanism, in which the NADPH was ligated in an extended fashion. Polar-mediated interactions dominated the interactions with the cofactor, which is atypical of the mode of NADPH binding within the AKR family. Moreover, the nicotinamide ring of NADPH was disordered, and this was attributed to the lack of an "AKR-conserved" bulky residue within the nicotinamide-binding cavity of MSMEG_2407. Enzymatic characterisation of MSMEG_2407 and Rv2971 identified dicarbonyls as a preferred substrate family for hydrolysis, and the frontline antituberculosis drug isoniazid (INH) was shown to inhibit the enzyme activity of both recombinant MSMEG_2407 and Rv2971. However, differences between the affinities of MSMEG_2407 and Rv2971 for dicarbonyls and INH were observed, and this was attributable to amino acid substitutions within the cofactor- and substrate-binding sites. The structures of MSMEG_2407 and the accompanying biochemical characterisation of MSMEG_2407 and Rv2971 provide insight into the structure and function of AKRs from mycobacteria.
Publisher: Springer Science and Business Media LLC
Date: 22-07-2012
DOI: 10.1038/NI.2372
Abstract: Natural killer T cells (NKT cells) are ided into type I and type II subsets on the basis of differences in their T cell antigen receptor (TCR) repertoire and CD1d-antigen specificity. Although the mode by which type I NKT cell TCRs recognize CD1d-antigen has been established, how type II NKT cell TCRs engage CD1d-antigen is unknown. Here we provide a basis for how a type II NKT cell TCR, XV19, recognized CD1d-sulfatide. The XV19 TCR bound orthogonally above the A' pocket of CD1d, in contrast to the parallel docking of type I NKT cell TCRs over the F' pocket of CD1d. At the XV19 TCR-CD1d-sulfatide interface, the TCRα and TCRβ chains sat centrally on CD1d, where the malleable CDR3 loops dominated interactions with CD1d-sulfatide. Accordingly, we highlight the erse mechanisms by which NKT cell TCRs can bind CD1d and account for the distinct antigen specificity of type II NKT cells.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-12-2019
Abstract: The ligands bound by γδ T cell receptors (TCRs) are less well characterized than those of their αβ TCR cousins, which are antigens presented by major histocompatibility complex (MHC) and related proteins. Le Nours et al. identified a phenotypically erse γδ T cell subset in human tissues that reacts to MHC-related protein 1 (MR1), which presents vitamin B derivatives. A crystal structure of a γδ TCR–MR1–antigen complex revealed that some of these TCRs can bind underneath the MR1 antigen-binding cleft instead of recognizing the presented antigen. This work thus uncovers an additional ligand for γδ T cells and reconceptualizes the nature of T cell antigen recognition. Science , this issue p. 1522
Publisher: Elsevier BV
Date: 12-2022
DOI: 10.1016/J.JBC.2022.102714
Abstract: The Major Histocompatibility Complex class I (MHC-I) related protein 1 (MR1) presents small molecule metabolites, drugs, and drug-like molecules that are recognized by MR1-reactive T cells. While we have an understanding of how antigens bind to MR1 and upregulate MR1 cell surface expression, a quantitative, cell-free, assessment of MR1-ligand binding affinity was lacking. Here, we developed a fluorescence polarization (FP)-based assay in which fluorescent MR1 ligand was loaded into MR1 protein in vitro, and competitively displaced by candidate ligands over a range of concentrations. Using this assay, ligand affinity for MR1 could be differentiated as strong (IC
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-07-2020
DOI: 10.1126/SCIIMMUNOL.ABC9492
Abstract: A rare human allele renders MR1 unable to present microbially derived antigen, resulting in a selective loss of MAIT cells.
Publisher: Proceedings of the National Academy of Sciences
Date: 29-11-2021
Abstract: Alongside αβ T cells and B cells, γδ T cells comprise a major component of the adaptive immune system, although a lack of bona fide ligands has hindered understanding of their function. γδ T cells are key mediators of epithelial immune surveillance and have a purported capacity for employing erse ligand engagement mechanisms beyond the dogmas of conventional αβ T cell–human leukocyte antigen restriction. Here, we found blood- and gut-resident Vδ1/2 − γδ T cells bound to MR1 tetramers in a metabolite-independent mechanism distinct from mucosal-associated invariant T cells and provide insight into a unique antibody-like MR1 recognition mode. This reshapes our understanding of the ligand recognition principles of γδ T cells and how they differ from αβ T cells.
Publisher: Springer Science and Business Media LLC
Date: 05-07-2022
DOI: 10.1038/S41467-022-31443-9
Abstract: CD1a is a monomorphic antigen-presenting molecule on dendritic cells that presents lipids to αβ T cells. Whether CD1a represents a ligand for other immune receptors remains unknown. Here we use CD1a tetramers to show that CD1a is a ligand for Vδ1 + γδ T cells. Functional studies suggest that two γδ T cell receptors (TCRs) bound CD1a in a lipid-independent manner. The crystal structures of three Vγ4Vδ1 TCR-CD1a-lipid complexes reveal that the γδ TCR binds at the extreme far side and parallel to the long axis of the β-sheet floor of CD1a’s antigen-binding cleft. Here, the γδ TCR co-recognises the CD1a heavy chain and β2 microglobulin in a manner that is distinct from all other previously observed γδ TCR docking modalities. The ‘sideways’ and lipid antigen independent mode of autoreactive CD1a recognition induces TCR clustering on the cell surface and proximal T cell signalling as measured by CD3ζ phosphorylation. In contrast with the ‘end to end’ binding of αβ TCRs that typically contact carried antigens, autoreactive γδ TCRs support geometrically erse approaches to CD1a, as well as antigen independent recognition.
Publisher: Springer Science and Business Media LLC
Date: 10-11-2021
Publisher: Wiley
Date: 16-12-2008
DOI: 10.1002/PROT.22310
Abstract: Microbial beta-1,4-galactanases are glycoside hydrolases belonging to family 53, which degrade galactan and arabinogalactan side chains in the hairy regions of pectin, a major plant cell wall component. They belong to the larger clan GH-A of glycoside hydrolases, which cover many different poly- and oligosaccharidase specificities. Crystallographic complexes of Bacillus licheniformis beta-1,4-galactanase and its inactive nucleophile mutant have been obtained with methyl-beta(1-->4)-galactotetraoside, providing, for the first time, information on substrate binding to the aglycone side of the beta-1,4-galactanase substrate binding groove. Using the experimentally determined subsites as a starting point, a beta(1-->4)-galactononaose was built into the structure and subjected to molecular dynamics simulations giving further insight into the residues involved in the binding of the polysaccharide from subsite -4 to +5. In particular, this analysis newly identified a conserved beta-turn, which contributes to subsites -2 to +3. This beta-turn is unique to family 53 beta-1,4-galactanases among all clan GH-A families that have been structurally characterized and thus might be a structural signature for endo-beta-1,4-galactanase specificity.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 26-03-2021
Abstract: The two established T cell lineages found in jawed vertebrates use either an αβ or a γδ T cell receptor (TCR) to detect antigens. Recently, another type of TCR chain (TCRµ) was found in marsupials and monotremes. Morrissey et al. analyzed T cells from the gray short-tailed opossum and uncovered a third lineage resident in the spleen that uses a γµ TCR (see the Perspective by Criscitiello). The authors then characterized the crystal structures of two different γµ TCRs, which exhibited an architecture distinct from αβ or γδ TCRs in which a highly erse, unpaired immunoglobulin-like variable domain was predicted to be the major antigen recognition determinant. Like camelid VHH and shark IgNAR antibodies, γµ TCRs could potentially inform future nanobody development. Science , this issue p. 1383 see also p. 1308
Publisher: Wiley
Date: 04-2004
DOI: 10.1110/PS.03533004
Publisher: American Society for Clinical Investigation
Date: 04-01-2021
DOI: 10.1172/JCI140706
Publisher: Rockefeller University Press
Date: 07-05-2021
DOI: 10.1084/JEM.20202699
Abstract: We optimized lipidomics methods to broadly detect endogenous lipids bound to cellular CD1a proteins. Whereas membrane phospholipids dominate in cells, CD1a preferentially captured sphingolipids, especially a C42, doubly unsaturated sphingomyelin (42:2 SM). The natural 42:2 SM but not the more common 34:1 SM blocked CD1a tetramer binding to T cells in all human subjects tested. Thus, cellular CD1a selectively captures a particular endogenous lipid that broadly blocks its binding to TCRs. Crystal structures show that the short cellular SMs stabilized a triad of surface residues to remain flush with CD1a, but the longer lipids forced the phosphocholine group to ride above the display platform to hinder TCR approach. Whereas nearly all models emphasize antigen-mediated T cell activation, we propose that the CD1a system has intrinsic autoreactivity and is negatively regulated by natural endogenous inhibitors selectively bound in its cleft. Further, the detailed chemical structures of natural blockers could guide future design of therapeutic blockers of CD1a response.
Publisher: Springer Science and Business Media LLC
Date: 14-09-2020
DOI: 10.1038/S43018-020-00111-6
Abstract: Antibody-mediated modulation of major histocompatibility complex (MHC) molecules, or MHC class I-like molecules, could constitute an effective immunotherapeutic approach. We describe how single-domain antibodies (VHH), specific for the human MHC class I-like molecule CD1d, can modulate the function of CD1d-restricted T cells and how one VHH (1D12) specifically induced strong type I natural killer T (NKT) cell activation. The crystal structure of the VHH1D12-CD1d(α-GalCer)-NKT T-cell receptor (TCR) complex revealed that VHH1D12 simultaneously contacted CD1d and the type I NKT TCR, thereby stabilizing this interaction through intrinsic bispecificity. This led to greatly enhanced type I NKT cell-mediated antitumor activity in in vitro, including multiple myeloma and acute myeloid leukemia patient-derived bone marrow s les, and in vivo models. Our findings underscore the versatility of VHH molecules in targeting composite epitopes, in this case consisting of a complexed monomorphic antigen-presenting molecule and an invariant TCR, and represent a generalizable antitumor approach.
Publisher: Elsevier BV
Date: 09-2010
Publisher: Wiley
Date: 06-2003
DOI: 10.1110/PS.0300103
Abstract: beta-1,4-Galactanases hydrolyze the galactan side chains that are part of the complex carbohydrate structure of the pectin. They are assigned to family 53 of the glycoside hydrolases and display significant variations in their pH and temperature optimum and stability. Two fungal beta-1,4-galactanases from Myceliophthora thermophila and Humicola insolens have been cloned and heterologously expressed, and the crystal structures of the gene products were determined. The structures are compared to the previously only known family 53 structure of the galactanase from Aspergillus aculeatus (AAGAL) showing approximately 56% identity. The M. thermophila and H. insolens galactanases are thermophilic enzymes and are most active at neutral to basic pH, whereas AAGAL is mesophilic and most active at acidic pH. The structure of the M. thermophila galactanase (MTGAL) was determined from crystals obtained with HEPES and TRIS buffers to 1.88 A and 2.14 A resolution, respectively. The structure of the H. insolens galactanase (HIGAL) was determined to 2.55 A resolution. The thermostability of MTGAL and HIGAL correlates with increase in the protein rigidity and electrostatic interactions, stabilization of the alpha-helices, and a tighter packing. An inspection of the active sites in the three enzymes identifies several amino acid substitutions that could explain the variation in pH optimum. Examination of the activity as a function of pH for the D182N mutant of AAGAL and the A90S/ H91D mutant of MTGAL showed that the difference in pH optimum between AAGAL and MTGAL is at least partially associated with differences in the nature of residues at positions 182, 90, and/or 91.
Publisher: Springer Science and Business Media LLC
Date: 15-02-2016
DOI: 10.1038/NCOMMS10570
Abstract: Crucial to Natural Killer T (NKT) cell function is the interaction between their T-cell receptor (TCR) and CD1d-antigen complex. However, the ersity of the NKT cell repertoire and the ensuing interactions with CD1d-antigen remain unclear. We describe an atypical population of CD1d–α-galactosylceramide (α-GalCer)-reactive human NKT cells that differ markedly from the prototypical TRAV10-TRAJ18-TRBV25-1 + type I NKT cell repertoire. These cells express a range of TCR α- and β-chains that show differential recognition of glycolipid antigens. Two atypical NKT TCRs (TRAV21-TRAJ8-TRBV7–8 and TRAV12-3-TRAJ27-TRBV6-5) bind orthogonally over the A′-pocket of CD1d, adopting distinct docking modes that contrast with the docking mode of all type I NKT TCR-CD1d-antigen complexes. Moreover, the interactions with α-GalCer differ between the type I and these atypical NKT TCRs. Accordingly, erse NKT TCR repertoire usage manifests in varied docking strategies and specificities towards CD1d–α-GalCer and related antigens, thus providing far greater scope for erse glycolipid antigen recognition.
Publisher: The American Association of Immunologists
Date: 15-09-2015
Abstract: Semi-invariant/type I NKT cells are a well-characterized CD1d-restricted T cell subset. The availability of potent Ags and tetramers for semi-invariant/type I NKT cells allowed this population to be extensively studied and revealed their central roles in infection, autoimmunity, and tumor immunity. In contrast, erse/type II NKT (dNKT) cells are poorly understood because the lipid Ags that they recognize are largely unknown. We sought to identify dNKT cell lipid Ag(s) by interrogating a panel of dNKT mouse cell hybridomas with lipid extracts from the pathogen Listeria monocytogenes. We identified Listeria phosphatidylglycerol as a microbial Ag that was significantly more potent than a previously characterized dNKT cell Ag, mammalian phosphatidylglycerol. Further, although mammalian phosphatidylglycerol-loaded CD1d tetramers did not stain dNKT cells, the Listeria-derived phosphatidylglycerol-loaded tetramers did. The structure of Listeria phosphatidylglycerol was distinct from mammalian phosphatidylglycerol because it contained shorter, fully-saturated anteiso fatty acid lipid tails. CD1d-binding lipid-displacement studies revealed that the microbial phosphatidylglycerol Ag binds significantly better to CD1d than do counterparts with the same headgroup. These data reveal a highly potent microbial lipid Ag for a subset of dNKT cells and provide an explanation for its increased Ag potency compared with the mammalian counterpart.
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.SEMCDB.2017.11.002
Abstract: Lipids are now widely considered to play a variety of important roles in T-cell mediated immunity, including serving as antigens. Lipid-based antigens are presented by a specialised group of glycoproteins termed CD1. In humans, three classes of CD1 molecules exist: group 1 (CD1a, CD1b, CD1c), group 2 (CD1d), and group 3 (CD1e). While CD1d-mediated T-cell immunity has been extensively investigated, we have only recently gained insights into the structure and function of group 1 CD1 molecules. Structural studies have revealed how lipid-based antigens are presented by group 1 CD1 molecules, as well as shedding light on the molecular requirements for T-cell recognition. Here, we provide an overview of our current understanding of lipid presentation by group 1 CD1 molecules in humans and their recognition by T-cells, as well as examining the potential differences in lipid presentation that may occur across different species.
Publisher: Elsevier BV
Date: 10-2020
Publisher: The American Association of Immunologists
Date: 15-12-2019
Abstract: High-throughput TCR sequencing allows interrogation of the human TCR repertoire, potentially connecting TCR sequences to antigenic targets. Unlike the highly polymorphic MHC proteins, monomorphic Ag-presenting molecules such as MR1, CD1d, and CD1b present Ags to T cells with species-wide TCR motifs. CD1b tetramer studies and a survey of the 27 published CD1b-restricted TCRs demonstrated a TCR motif in humans defined by the TCR β-chain variable gene 4-1 (TRBV4-1) region. Unexpectedly, TRBV4-1 was involved in recognition of CD1b regardless of the chemical class of the carried lipid. Crystal structures of two CD1b-specific TRBV4-1+ TCRs show that germline-encoded residues in CDR1 and CDR3 regions of TRBV4-1–encoded sequences interact with each other and consolidate the surface of the TCR. Mutational studies identified a key positively charged residue in TRBV4-1 and a key negatively charged residue in CD1b that is shared with CD1c, which is also recognized by TRBV4-1 TCRs. These data show that one TCR V region can mediate a mechanism of recognition of two related monomorphic Ag-presenting molecules that does not rely on a defined lipid Ag.
Publisher: American Chemical Society (ACS)
Date: 27-08-2005
DOI: 10.1021/BI050779V
Abstract: The endo-beta-1,4-mannanase from the soil bacterium Cellulomonas fimi is a modular plant cell wall degrading enzyme involved in the hydrolysis of the backbone of mannan, one of the most abundant polysaccharides of the hemicellulosic network in the plant cell wall. The crystal structure of a recombinant truncated endo-beta-1,4-mannanase from C. fimi (CfMan26A-50K) was determined by X-ray crystallography to 2.25 A resolution using the molecular replacement technique. The overall structure of the enzyme consists of a core (beta/alpha)8-barrel catalytic module characteristic of clan GH-A, connected via a linker to an immunoglobulin-like module of unknown function. A complex with the oligosaccharide mannotriose to 2.9 A resolution has also been obtained. Both the native structure and the complex show a cacodylate ion bound at the -1 subsite, while subsites -2, -3, and -4 are occupied by mannotriose in the complex. Enzyme kinetic analysis and the analysis of hydrolysis products from manno-oligosaccharides and mannopentitol suggest five important active-site cleft subsites. CfMan26A-50K has a high affinity -3 subsite with Phe325 as an aromatic platform, which explains the mannose releasing property of the enzyme. Structural differences with the homologous Cellvibrio japonicus beta-1,4-mannanase (CjMan26A) at the -2 and -3 subsites may explain the poor performance of CfMan26A mutants as "glycosynthases".
Publisher: Elsevier BV
Date: 05-2018
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-01-2020
DOI: 10.1126/SCIIMMUNOL.AAX5430
Abstract: CD1a, an abundant lipid antigen–presenting molecule in human skin, mediates T cell responses to small contact allergens.
Publisher: MDPI AG
Date: 05-03-2021
DOI: 10.3390/IJMS22052617
Abstract: T cells represent a critical arm of our immune defense against pathogens. Over the past two decades, considerable inroads have been made in understanding the fundamental principles underpinning the molecular presentation of peptide-based antigens by the Major Histocompatibility Complex molecules (MHC-I and II), and their molecular recognition by specialized subsets of T cells. However, some T cells can recognize lipid-based antigens presented by MHC-I-like molecules that belong to the Cluster of Differentiation 1 (CD1) family. Here, we will review the advances that have been made in the last five years to understand the molecular mechanisms orchestrating the presentation of novel endogenous and exogenous lipid-based antigens by the CD1 glycoproteins and their recognition by specific populations of CD1-reactive T cells.
Publisher: Rockefeller University Press
Date: 26-08-2022
DOI: 10.1084/JEM.20210828
Abstract: Mucosal-associated invariant T (MAIT) cells detect microbial infection via recognition of riboflavin-based antigens presented by the major histocompatibility complex class I (MHC-I)–related protein 1 (MR1). Most MAIT cells in human peripheral blood express CD8αα or CD8αβ coreceptors, and the binding site for CD8 on MHC-I molecules is relatively conserved in MR1. Yet, there is no direct evidence of CD8 interacting with MR1 or the functional consequences thereof. Similarly, the role of CD8αα in lymphocyte function remains ill-defined. Here, using newly developed MR1 tetramers, mutated at the CD8 binding site, and by determining the crystal structure of MR1–CD8αα, we show that CD8 engaged MR1, analogous to how it engages MHC-I molecules. CD8αα and CD8αβ enhanced MR1 binding and cytokine production by MAIT cells. Moreover, the CD8–MR1 interaction was critical for the recognition of folate-derived antigens by other MR1-reactive T cells. Together, our findings suggest that both CD8αα and CD8αβ act as functional coreceptors for MAIT and other MR1-reactive T cells.
Publisher: Springer Science and Business Media LLC
Date: 22-08-2016
DOI: 10.1038/NI.3523
Publisher: Wiley
Date: 27-02-2018
DOI: 10.1111/IMCB.12017
Abstract: The major histocompatibility complex (MHC) class-I related molecule MR1 is a monomorphic and evolutionary conserved antigen (Ag)-presenting molecule that shares the overall architecture of MHC-I and CD1 proteins. However, in contrast to MHC-I and the CD1 family that present peptides and lipids, respectively, MR1 specifically presents small organic molecules. During microbial infection of mammalian cells, MR1 captures and presents vitamin B precursors, derived from the microbial biosynthesis of riboflavin, on the surface of antigen-presenting cells. These MR1-Ag complexes are recognized by the mucosal-associated invariant T cell receptor (MAIT TCR), which subsequently leads to MAIT cell activation. Recently, MR1 was shown to trap chemical scaffolds including drug and drug-like molecules. Here, we review this metabolite Ag-presenting molecule and further define the key molecular interactions underlying the recognition and reactivity of MAIT TCRs to MR1 in an Ag-dependent manner.
Publisher: Rockefeller University Press
Date: 12-2014
DOI: 10.1084/JEM.20141764
Abstract: αβ and γδ T cells are disparate T cell lineages that can respond to distinct antigens (Ags) via the use of the αβ and γδ T cell Ag receptors (TCRs), respectively. Here we characterize a population of human T cells, which we term δ/αβ T cells, expressing TCRs comprised of a TCR-δ variable gene (Vδ1) fused to joining α and constant α domains, paired with an array of TCR-β chains. We demonstrate that these cells, which represent ∼50% of all Vδ1+ human T cells, can recognize peptide- and lipid-based Ags presented by human leukocyte antigen (HLA) and CD1d, respectively. Similar to type I natural killer T (NKT) cells, CD1d-lipid Ag-reactive δ/αβ T cells recognized α-galactosylceramide (α-GalCer) however, their fine specificity for other lipid Ags presented by CD1d, such as α-glucosylceramide, was distinct from type I NKT cells. Thus, δ/αβTCRs contribute new patterns of Ag specificity to the human immune system. Furthermore, we provide the molecular bases of how δ/αβTCRs bind to their targets, with the Vδ1-encoded region providing a major contribution to δ/αβTCR binding. Our findings highlight how components from αβ and γδTCR gene loci can recombine to confer Ag specificity, thus expanding our understanding of T cell biology and TCR ersity.
Publisher: Springer Science and Business Media LLC
Date: 29-09-2013
DOI: 10.1038/NI.2713
Abstract: The T cell repertoire comprises αβ and γδ T cell lineages. Although it is established how αβ T cell antigen receptors (TCRs) interact with antigen presented by antigen-presenting molecules, this is unknown for γδ TCRs. We describe a population of human Vδ1(+) γδ T cells that exhibit autoreactivity to CD1d and provide a molecular basis for how a γδ TCR binds CD1d-α-galactosylceramide (α-GalCer). The γδ TCR docked orthogonally, over the A' pocket of CD1d, in which the Vδ1-chain, and in particular the germ line-encoded CDR1δ loop, dominated interactions with CD1d. The TCR γ-chain sat peripherally to the interface, with the CDR3γ loop representing the principal determinant for α-GalCer specificity. Accordingly, we provide insight into how a γδ TCR binds specifically to a lipid-loaded antigen-presenting molecule.
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1016/J.STR.2009.11.014
Abstract: Many pathogenic bacteria have sophisticated mechanisms to interfere with the mammalian immune response. These include the disruption of host extracellular ATP levels that, in humans, is tightly regulated by the nucleoside triphosphate diphosphohydrolase family (NTPDases). NTPDases are found almost exclusively in eukaryotes, the notable exception being their presence in some pathogenic prokaryotes. To address the function of bacterial NTPDases, we describe the structures of an NTPDase from the pathogen Legionella pneumophila (Lpg1905/Lp1NTPDase) in its apo state and in complex with the ATP analog AMPPNP and the subtype-specific NTPDase inhibitor ARL 67156. Lp1NTPDase is structurally and catalytically related to eukaryotic NTPDases and the structure provides a basis for NTPDase-specific inhibition. Furthermore, we demonstrate that the activity of Lp1NTPDase correlates directly with intracellular replication of Legionella within macrophages. Collectively, these findings provide insight into the mechanism of this enzyme and highlight its role in host-pathogen interactions.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-07-2020
Abstract: Integrating comparative immunology can improve human, animal, and ecosystem health
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1016/J.STR.2013.08.024
Abstract: AB5 toxins are composed of an enzymatic A subunit that disrupts cellular function associated with a pentameric B subunit required for host cell invasion. EcxAB is an AB5 toxin isolated from clinical strains of Escherichia coli classified as part of the cholera family due to B subunit homology. Cholera-group toxins have catalytic ADP-ribosyltransferases as their A subunits, so it was surprising that EcxA did not. We confirmed that EcxAB self-associates as a functional toxin and obtained its structure. EcxAB is a prototypical member of a hybrid AB5 toxin family containing metzincin-type metalloproteases as their active A subunit paired to a cholera-like B subunit. Furthermore, EcxA is distinct from previously characterized proteases and thus founds an AB5-associated metzincin family that we term the toxilysins. EcxAB provides the first observation of conserved B subunit usage across different AB5 toxin families and provides evidence that the intersubunit interface of these toxins is far more permissive than previously supposed.
Publisher: Springer Science and Business Media LLC
Date: 20-11-2019
DOI: 10.1038/S41467-019-12941-9
Abstract: Type I and type II natural killer T (NKT) cells are restricted to the lipid antigen-presenting molecule CD1d. While we have an understanding of the antigen reactivity and function of type I NKT cells, our knowledge of type II NKT cells in health and disease remains unclear. Here we describe a population of type II NKT cells that recognise and respond to the microbial antigen, α-glucuronosyl-diacylglycerol (α-GlcADAG) presented by CD1d, but not the prototypical type I NKT cell agonist, α-galactosylceramide. Surprisingly, the crystal structure of a type II NKT TCR-CD1d-α-GlcADAG complex reveals a CD1d F’-pocket-docking mode that contrasts sharply with the previously determined A’-roof positioning of a sulfatide-reactive type II NKT TCR. Our data also suggest that erse type II NKT TCRs directed against distinct microbial or mammalian lipid antigens adopt multiple recognition strategies on CD1d, thereby maximising the potential for type II NKT cells to detect different lipid antigens.
Publisher: International Union of Crystallography (IUCr)
Date: 27-07-2013
Publisher: Springer Science and Business Media LLC
Date: 31-07-2011
DOI: 10.1038/NI.2076
Publisher: Elsevier BV
Date: 09-2013
Publisher: Springer Science and Business Media LLC
Date: 12-03-2018
Publisher: Elsevier BV
Date: 05-2021
Publisher: Springer Science and Business Media LLC
Date: 11-07-2013
DOI: 10.1038/NCOMMS3142
Abstract: The mucosal-associated invariant T-cell antigen receptor (MAIT TCR) recognizes MR1 presenting vitamin B metabolites. Here we describe the structures of a human MAIT TCR in complex with human MR1 presenting a non-stimulatory ligand derived from folic acid and an agonist ligand derived from a riboflavin metabolite. For both vitamin B antigens, the MAIT TCR docks in a conserved manner above MR1, thus acting as an innate-like pattern recognition receptor. The invariant MAIT TCR α-chain usage is attributable to MR1-mediated interactions that prise open the MR1 cleft to allow contact with the vitamin B metabolite. Although the non-stimulatory antigen does not contact the MAIT TCR, the stimulatory antigen does. This results in a higher affinity of the MAIT TCR for a stimulatory antigen in comparison with a non-stimulatory antigen. We formally demonstrate a structural basis for MAIT TCR recognition of vitamin B metabolites, while illuminating how TCRs recognize microbial metabolic signatures.
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.IMMUNI.2018.03.009
Abstract: Most studies on the immunotherapeutic potential of T cells have focused on CD8 and CD4 T cells that recognize peptide antigens (Ag) presented by polymorphic major histocompatibility complex (MHC) class I and MHC class II molecules, respectively. However, unconventional T cells, which interact with MHC class Ib and MHC-I like molecules, are also implicated in tumor immunity, although their role therein is unclear. These include unconventional T cells targeting MHC class Ib molecules such as HLA-E and its murine ortholog Qa-1b, natural killer T (NKT) cells, mucosal associated invariant T (MAIT) cells, and γδ T cells. Here, we review the current understanding of the roles of these unconventional T cells in tumor immunity and discuss why further studies into the immunotherapeutic potential of these cells is warranted.
Publisher: Elsevier BV
Date: 11-2011
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.IMMUNI.2015.12.005
Abstract: A characteristic of mucosal-associated invariant T (MAIT) cells is the expression of TRAV1-2(+) T cell receptors (TCRs) that are activated by riboflavin metabolite-based antigens (Ag) presented by the MHC-I related molecule, MR1. Whether the MR1-restricted T cell repertoire and associated Ag responsiveness extends beyond these cells remains unclear. Here, we describe MR1 autoreactivity and folate-derivative reactivity in a discrete subset of TRAV1-2(+) MAIT cells. This recognition was attributable to CDR3β loop-mediated effects within a consensus TRAV1-2(+) TCR-MR1-Ag footprint. Furthermore, we have demonstrated differential folate- and riboflavin-derivative reactivity by a erse population of "atypical" TRAV1-2(-) MR1-restricted T cells. We have shown that TRAV1-2(-) T cells are phenotypically heterogeneous and largely distinct from TRAV1-2(+) MAIT cells. A TRAV1-2(-) TCR docks more centrally on MR1, thereby adopting a markedly different molecular footprint to the TRAV1-2(+) TCR. Accordingly, ersity within the MR1-restricted T cell repertoire leads to differing MR1-restricted Ag specificity.
Publisher: Springer Science and Business Media LLC
Date: 02-03-2020
Publisher: Elsevier BV
Date: 09-2011
DOI: 10.1016/J.CARRES.2011.05.017
Abstract: β-1,4-Galactanases belong to glycoside hydrolase family GH 53 and degrade galactan and arabinogalactan side chains of the complex pectin network in plant cell walls. Two fungal β-1,4-galactanases from Aspergillus aculeatus, Meripileus giganteus and one bacterial enzyme from Bacillus licheniformis have been kinetically characterized using the chromogenic substrate analog 4-nitrophenyl β-1,4-d-thiogalactobioside synthesized by the thioglycoligase approach. Values of k(cat)/K(m) for this substrate with A. aculeatus β-1,4-galactanase at pH 4.4 and for M. giganteus β-1,4-galactanase at pH 5.5 are 333M(-1)s(-1) and 62M(-1)s(-1), respectively. By contrast the B. licheniformis β-1,4-galactanase did not hydrolyze 4-nitrophenyl β-1,4-d-thiogalactobioside. The different kinetic behavior observed between the two fungal and the bacterial β-1,4-galactanases can be ascribed to an especially long loop 8 observed only in the structure of B. licheniformis β-1,4-galactanase. This loop contains substrate binding subsites -3 and -4, which presumably cause B. licheniformis β-1,4-galactanase to bind 4-nitrophenyl -1,4-β-d-thiogalactobioside non-productively. In addition to their cleavage of 4-nitrophenyl -1,4-β-d-thiogalactobioside, the two fungal enzymes also cleaved the commercially available 2-nitrophenyl-1,4-β-d-galactopyranoside, but kinetic parameters could not be determined because of transglycosylation at substrate concentrations above 4mM.
Publisher: Springer Science and Business Media LLC
Date: 16-01-2018
Start Date: 2021
End Date: 12-2024
Amount: $721,970.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2017
End Date: 06-2020
Amount: $428,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2017
End Date: 12-2022
Amount: $679,756.00
Funder: Australian Research Council
View Funded Activity