RESUMO
The CD1 family of antigen-presenting molecules adopt a major histocompatibility complex class I (MHC-I) fold. Whereas MHC molecules present peptides, the CD1 family has evolved to bind self- and foreign-lipids. The CD1 family of antigen-presenting molecules comprises four members-CD1a, CD1b, CD1c, and CD1d-that differ in their architecture around the lipid-binding cleft, thereby enabling diverse lipids to be accommodated. These CD1-lipid complexes are recognized by T cell receptors (TCRs) expressed on T cells, either through dual recognition of CD1 and lipid or in a new model whereby the TCR directly contacts CD1, thereby triggering an immune response. Chemical syntheses of lipid antigens, and analogs thereof, have been crucial in understanding the underlying specificity of T cell-mediated lipid immunity. This review will focus on our current understanding of how TCRs interact with CD1-lipid complexes, highlighting how it can be fundamentally different from TCR-MHC-peptide corecognition.
RESUMO
BACKGROUND: CD1d is a monomorphic major histocompatibility complex class I-like molecule that presents lipid antigens to distinct T-cell subsets and can be expressed by various malignancies. Antibody-mediated targeting of CD1d on multiple myeloma cells was reported to induce apoptosis and could therefore constitute a novel therapeutic approach. METHODS: To determine how a CD1d-specific single-domain antibody (VHH) enhances binding of the early apoptosis marker annexin V to CD1d+ tumor cells we use in vitro cell-based assays and CRISPR-Cas9-mediated gene editing, and to determine the structure of the VHH1D17-CD1d(endogenous lipid) complex we use X-ray crystallography. RESULTS: Anti-CD1d VHH1D17 strongly enhances annexin V binding to CD1d+ tumor cells but this does not reflect induction of apoptosis. Instead, we show that VHH1D17 enhances presentation of phosphatidylserine (PS) in CD1d and that this is saposin dependent. The crystal structure of the VHH1D17-CD1d(endogenous lipid) complex demonstrates that VHH1D17 binds the A'-pocket of CD1d, leaving the lipid headgroup solvent exposed, and has an electro-negatively charged patch which could be involved in the enhanced PS presentation by CD1d. Presentation of PS in CD1d does not trigger phagocytosis but leads to greatly enhanced binding of T-cell immunoglobulin and mucin domain containing molecules (TIM)-1 to TIM-3, TIM-4 and induces TIM-3 signaling. CONCLUSION: Our findings reveal the existence of an immune modulatory CD1d(PS)-TIM axis with potentially unexpected implications for immune regulation in both physiological and pathological conditions.
Assuntos
Receptor Celular 2 do Vírus da Hepatite A , Anticorpos de Domínio Único , Humanos , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Anticorpos de Domínio Único/metabolismo , Fosfatidilserinas/metabolismo , Anexina A5 , Subpopulações de Linfócitos TRESUMO
The CD1 system binds lipid antigens for display to T cells. Here, we solved lipidomes for the four human CD1 antigen-presenting molecules, providing a map of self-lipid display. Answering a basic question, the detection of >2,000 CD1-lipid complexes demonstrates broad presentation of self-sphingolipids and phospholipids. Whereas peptide antigens are chemically processed, many lipids are presented in an unaltered form. However, each type of CD1 protein differentially edits the self-lipidome to show distinct capture motifs based on lipid length and chemical composition, suggesting general antigen display mechanisms. For CD1a and CD1d, lipid size matches the CD1 cleft volume. CD1c cleft size is more variable, and CD1b is the outlier, where ligands and clefts show an extreme size mismatch that is explained by uniformly seating two small lipids in one cleft. Furthermore, the list of compounds that comprise the integrated CD1 lipidome supports the ongoing discovery of lipid blockers and antigens for T cells.
Assuntos
Antígenos CD1 , Lipídeos , Humanos , Apresentação de Antígeno , Antígenos CD1/química , Antígenos CD1/metabolismo , Lipidômica , Lipídeos/química , Linfócitos T , Motivos de AminoácidosRESUMO
After two decades of the study of lipid antigens that activate CD1-restricted T cells, new studies show how autoreactive αß T-cell receptors (TCRs) can directly recognize the outer surface of CD1 proteins in ways that are lipid-agnostic. Most recently, this lipid agnosticism has turned to negativity, with the discovery of natural CD1 ligands that dominantly negatively block autoreactive αß TCR binding to CD1a and CD1d. This review highlights the basic differences between positive and negative regulation of cellular systems. We outline strategies to discover lipid inhibitors of CD1-reactive T cells, whose roles in vivo are becoming clear, especially in CD1-mediated skin disease.
Assuntos
Apresentação de Antígeno , Linfócitos T , Humanos , Receptores de Antígenos de Linfócitos T/metabolismo , Antígenos , Lipídeos , Antígenos CD1/metabolismoRESUMO
CD1 glycoproteins present lipid-based antigens to T-cell receptors (TCRs). A role for CD1b in T-cell-mediated autoreactivity was proposed when it was established that CD1b can present self-phospholipids with short alkyl chains (â¼C34) to T cells; however, the structural characteristics of this presentation and recognition are unclear. Here, we report the 1.9 Å resolution binary crystal structure of CD1b presenting a self-phosphatidylinositol-C34:1 and an endogenous scaffold lipid. Moreover, we also determined the 2.4 Å structure of CD1b-phosphatidylinositol complexed to an autoreactive αß TCR, BC8B. We show that the TCR docks above CD1b and directly contacts the presented antigen, selecting for both the phosphoinositol headgroup and glycerol neck region via antigen remodeling within CD1b and allowing lateral escape of the inositol moiety through a channel formed by the TCR α-chain. Furthermore, through alanine scanning mutagenesis and surface plasmon resonance, we identified key CD1b residues mediating this interaction, with Glu-80 abolishing TCR binding. We in addition define a role for both CD1b α1 and CD1b α2 molecular domains in modulating this interaction. These findings suggest that the BC8B TCR contacts both the presented phospholipid and the endogenous scaffold lipid via a dual mechanism of corecognition. Taken together, these data expand our understanding into the molecular mechanisms of CD1b-mediated T-cell autoreactivity.
Assuntos
Apresentação de Antígeno , Antígenos CD1 , Fosfatidilinositóis , Receptores de Antígenos de Linfócitos T , Linfócitos T , Antígenos CD1/metabolismo , Fosfolipídeos/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/metabolismoRESUMO
Expressed on epidermal Langerhans cells, CD1a presents a range of self-lipid antigens found within the skin; however, the extent to which CD1a presents microbial ligands from bacteria colonizing the skin is unclear. Here we identified CD1a-dependent T cell responses to phosphatidylglycerol (PG), a ubiquitous bacterial membrane phospholipid, as well as to lysylPG, a modified PG, present in several Gram-positive bacteria and highly abundant in Staphylococcus aureus. The crystal structure of the CD1a-PG complex showed that the acyl chains were buried within the A'- and F'-pockets of CD1a, while the phosphoglycerol headgroup remained solvent exposed in the F'-portal and was available for T cell receptor contact. Using lysylPG and PG-loaded CD1a tetramers, we identified T cells in peripheral blood and in skin that respond to these lipids in a dose-dependent manner. Tetramer+CD4+ T cell lines secreted type 2 helper T cell cytokines in response to phosphatidylglycerols as well as to co-cultures of CD1a+ dendritic cells and Staphylococcus bacteria. The expansion in patients with atopic dermatitis of CD4+ CD1a-(lysyl)PG tetramer+ T cells suggests a response to lipids made by bacteria associated with atopic dermatitis and provides a link supporting involvement of PG-based lipid-activated T cells in atopic dermatitis pathogenesis.
Assuntos
Dermatite Atópica , Humanos , Pele , Células de Langerhans , Antígenos CD1 , Autoantígenos/metabolismo , Staphylococcus/metabolismo , FosfatidilgliceróisRESUMO
Whereas proteolytic cleavage is crucial for peptide presentation by classical major histocompatibility complex (MHC) proteins to T cells, glycolipids presented by CD1 molecules are typically presented in an unmodified form. However, the mycobacterial lipid antigen mannosyl-ß1-phosphomycoketide (MPM) may be processed through hydrolysis in antigen presenting cells, forming mannose and phosphomycoketide (PM). To further test the hypothesis that some lipid antigens are processed, and to generate antigens that lead to defined epitopes for future tuberculosis vaccines or diagnostic tests, we aimed to create hydrolysis-resistant MPM variants that retain their antigenicity. Here, we designed and tested three different, versatile synthetic strategies to chemically stabilize MPM analogs. Crystallographic studies of CD1c complexes with these three new MPM analogs showed anchoring of the lipid tail and phosphate group that is highly comparable to nature-identical MPM, with considerable conformational flexibility for the mannose head group. MPM-3, a difluoromethylene-modified version of MPM that is resistant to hydrolysis, showed altered recognition by cells, but not by CD1c proteins, supporting the cellular antigen processing hypothesis. Furthermore, the synthetic analogs elicited T cell responses that were cross-reactive with nature-identical MPM, fulfilling important requirements for future clinical use.
Assuntos
Antígenos de Bactérias/química , Antígenos CD1/química , Glicolipídeos/química , Glicoproteínas/química , Mycobacterium tuberculosis/química , Fosfolipídeos/química , Linfócitos T/química , Antígenos de Bactérias/imunologia , Antígenos CD1/imunologia , Linhagem Celular Transformada , Cristalografia por Raios X , Glicolipídeos/imunologia , Glicoproteínas/imunologia , Humanos , Mycobacterium tuberculosis/imunologia , Fosfolipídeos/imunologia , Linfócitos T/imunologiaRESUMO
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.
Assuntos
Antígenos CD1/imunologia , Antígenos/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Lipídeos/imunologia , Ativação Linfocitária , Linfócitos T/imunologia , HumanosRESUMO
γδ T cells form an abundant part of the human cellular immune system, where they respond to tissue damage, infection, and cancer. The spectrum of known molecular targets recognized by Vδ1-expressing γδ T cells is becoming increasingly diverse. Here we describe human γδ T cells that recognize CD1b, a lipid antigen-presenting molecule, which is inducibly expressed on monocytes and dendritic cells. Using CD1b tetramers to study multiple donors, we found that many CD1b-specific γδ T cells use Vδ1. Despite their common use of Vδ1, three CD1b-specific γδ T cell receptors (TCRs) showed clear differences in the surface of CD1b recognized, the requirement for lipid antigens, and corecognition of butryophilin-like proteins. Several Vγ segments were present among the CD1b-specific TCRs, but chain swap experiments demonstrated that CD1b specificity was mediated by the Vδ1 chain. One of the CD1b-specific Vδ1+ TCRs paired with Vγ4 and shows dual reactivity to CD1b and butyrophilin-like proteins. αß TCRs typically recognize the peptide display platform of MHC proteins. In contrast, our results demonstrate the use of rearranged receptors to mediate diverse modes of recognition across the surface of CD1b in ways that do and do not require carried lipids.
Assuntos
Antígenos CD1/metabolismo , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/metabolismo , Apresentação de Antígeno , Antígenos CD1/imunologia , Cristalografia por Raios X/métodos , Humanos , Linfócitos Intraepiteliais/fisiologia , Lipídeos/imunologia , Ativação Linfocitária/imunologia , Modelos Moleculares , Monócitos/metabolismo , Linfócitos T/imunologiaRESUMO
Galectins are a family of glycan-binding molecules with a characteristic affinity for ß-D-glycosides that mediate a variety of important cellular functions, including immune and inflammatory responses. Galectin-11 (LGALS-11) has been recently identified as a mediator induced specifically in animals against gastrointestinal nematodes and can interfere with parasite growth and development. Here, we report that at least two natural genetic variants of LGALS-11 exist in sheep, and demonstrate fundamental differences in anti-parasitic activity, correlated with their ability to dimerise. This study improves our understanding of the role of galectins in the host immune and inflammatory responses against parasitic nematodes and provides a basis for genetic studies toward selective breeding of animals for resistance to parasites.
Assuntos
Antiparasitários/química , Antiparasitários/farmacologia , Galectinas/química , Galectinas/farmacologia , Multimerização Proteica , Sequência de Aminoácidos , Animais , Modelos Moleculares , Doenças Parasitárias em Animais/tratamento farmacológico , Doenças Parasitárias em Animais/parasitologia , Testes de Sensibilidade Parasitária , Conformação Proteica , Ovinos , Carneiro Doméstico , Relação Estrutura-AtividadeRESUMO
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 samples, 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.
Assuntos
Receptores de Antígenos de Linfócitos T , Antígenos CD1d/química , Humanos , Receptores de Antígenos de Linfócitos T/químicaRESUMO
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 ß-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.
Assuntos
Motivos de Aminoácidos , Antígenos CD1d/química , Antígenos CD1d/metabolismo , Sítios de Ligação , Receptores de Antígenos de Linfócitos T alfa-beta/química , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Apresentação de Antígeno , Sequência Conservada , Epitopos de Linfócito T/química , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/metabolismo , Rearranjo Gênico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunofenotipagem , Lipídeos/química , Modelos Moleculares , Mutação , Ligação Proteica , Conformação Proteica , Multimerização Proteica , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Relação Estrutura-Atividade , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
CD1 proteins are expressed on dendritic cells, where they display lipid antigens to T-cell receptors (TCRs). Here we describe T-cell autoreactivity towards ubiquitous human membrane phospholipids presented by CD1b. These T-cells discriminate between two major types of lipids, sphingolipids and phospholipids, but were broadly cross-reactive towards diverse phospholipids including phosphatidylcholine, phosphatidylinositol and phosphatidylethanolamine. The crystal structure of a representative TCR bound to CD1b-phosphatidylcholine provides a molecular mechanism for this promiscuous recognition. We observe a lateral escape channel in the TCR, which shunted phospholipid head groups sideways along the CD1b-TCR interface, without contacting the TCR. Instead the TCR recognition site involved the neck region phosphate that is common to all major self-phospholipids but absent in sphingolipids. Whereas prior studies have focused on foreign lipids or rare self-lipids, we define a new molecular mechanism of promiscuous recognition of common self-phospholipids including those that are known targets in human autoimmune disease.
Assuntos
Antígenos CD1/química , Fosfolipídeos/química , Receptores de Antígenos de Linfócitos T/química , Linfócitos T/fisiologia , Apresentação de Antígeno , Ligação Competitiva , Linhagem Celular , Membrana Celular/imunologia , Membrana Celular/metabolismo , Cristalografia por Raios X , Humanos , Modelos Imunológicos , Simulação de Acoplamento MolecularRESUMO
The CD1 family of glycoproteins are MHC class I-like molecules that present a wide array of self and foreign lipid antigens to T-cell receptors (TCRs) on T-cells. Humans express three classes of CD1 molecules, denoted as Group 1 (CD1a, CD1b, and CD1c), Group 2 (CD1d), and Group 3 (CD1e). Of the CD1 family of molecules, CD1b exhibits the largest and most complex antigen binding groove; allowing it the capabilities to present a broad spectrum of lipid antigens. While its role in foreign-lipid presentation in the context of mycobacterial infection are well characterized, understanding the roles of CD1b in autoreactivity are recently being elucidated. While the mechanisms governing proliferation of CD1b-restricted autoreactive T cells, regulation of CD1 gene expression, and the processes controlling CD1+ antigen presenting cell maturation are widely undercharacterized, the exploration of self-lipid antigens in the context of disease have recently come into focus. Furthermore, the recently expanded pool of CD1b crystal structures allow the opportunity to further analyze the molecular mechanisms of T-cell recognition and self-lipid presentation; where the intricacies of the two-compartment system, that accommodate both the presented self-lipid antigen and scaffold lipids, are scrutinized. This review delves into the immunological and molecular mechanisms governing presentation and T-cell recognition of the broad self-lipid repertoire of CD1b; with evidence mounting pointing towards a role in diseases such as microbial infection, autoimmune diseases, and cancer.
Assuntos
Apresentação de Antígeno , Antígenos CD1 , Autoantígenos , Lipídeos , Linfócitos T/imunologia , Animais , Antígenos CD1/química , Antígenos CD1/imunologia , Autoantígenos/química , Autoantígenos/imunologia , Cristalografia por Raios X , Humanos , Lipídeos/química , Lipídeos/imunologia , Relação Estrutura-AtividadeRESUMO
Peptide and lipid antigens are presented to T cells when bound to MHC or CD1 proteins, respectively. The general paradigm of T cell antigen recognition is that T cell receptors (TCRs) co-recognize an epitope comprised of the antigen and antigen presenting molecule. Here we review the latest studies in which T cells operate outside the co-recognition paradigm: TCRs can broadly contact CD1 itself, but not the carried lipid. The essential structural feature in these new mechanisms is a large 'antigen free' zone on the outer surface of certain antigen presenting molecules. Whereas peptides dominate the exposed surface of MHC-peptide complexes, all human CD1 proteins have a closed, antigen-free surface, which is known as the A' roof. These new structural models help to interpret recent biological studies of CD1 autoreactive T cells in vivo, which have now been broadly observed in studies on TCR-transgenic mice, healthy humans and patients with autoimmune disease.
Assuntos
Antígenos CD1/imunologia , Antígenos CD1/metabolismo , Autoimunidade , Lipídeos/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Apresentação de Antígeno , Antígenos/química , Antígenos/imunologia , Antígenos CD1/química , Humanos , Ligantes , Lipídeos/química , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/químicaRESUMO
The immune system has evolved to protect hosts from pathogens. T cells represent a critical component of the immune system by their engagement in host defence mechanisms against microbial infections. Our knowledge of the molecular recognition by T cells of pathogen-derived peptidic antigens that are presented by the major histocompatibility complex glycoproteins is now well established. However, lipids represent an additional, distinct chemical class of molecules that when presented by the family of CD1 antigen-presenting molecules can serve as antigens, and be recognized by specialized subsets of T cells leading to antigen-specific activation. Over the past decades, numerous CD1-presented self- and bacterial lipid-based antigens have been isolated and characterized. However, our understanding at the molecular level of T cell immunity to CD1 molecules presenting microbial lipid-based antigens is still largely unexplored. Here, we review the insights and the molecular basis underpinning the recognition of microbial lipid-based antigens by T cells.
Assuntos
Antígenos de Bactérias/imunologia , Antígenos CD1/imunologia , Bactérias/imunologia , Infecções Bacterianas/imunologia , Lipídeos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Animais , Interações Hospedeiro-Patógeno , Humanos , Imunidade Celular , Modelos MolecularesRESUMO
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.
Assuntos
Apresentação de Antígeno/imunologia , Antígenos CD1/metabolismo , Lipídeos/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD1/imunologia , Humanos , Glicoproteínas de Membrana/imunologiaRESUMO
Human T cell autoreactivity toward lipid antigens presented by CD1 proteins can manifest in numerous diseases, including psoriasis, contact hypersensitivities, and allergies. However, the molecular mechanisms for regulating T cell autoreactivity toward lipid antigens remain unclear. We determined the basis for T cell receptor (TCR) autoreactivity toward CD1b bound to self-phospholipids. The spectrum of self-antigens captured by CD1b skews toward abundant membrane phospholipids such as phosphatidylcholine and phosphatidylethanolamine. However, TCRs can specifically recognize rare phospholipids, including phosphatidylglycerol (PG). The structure of an autoreactive TCR bound to CD1b-PG shows that discrimination occurs through a marked induced fit movement of PG so that its polar head group fits snugly into the cationic cup of the TCR. Conversely, TCR binding toward ubiquitous self-phospholipids was sterically or electrostatically repelled. Accordingly, we describe a mechanism of TCR autoreactivity toward rare phospholipids and avoidance of autoreactivity to the most abundant self-phospholipids.
Assuntos
Autoantígenos/imunologia , Fosfolipídeos/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Antígenos CD1/imunologia , Antígenos CD1/metabolismo , Humanos , Células K562 , Ativação Linfocitária , Camundongos , Fosfatidilcolinas/imunologia , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/imunologia , Fosfatidiletanolaminas/metabolismo , Fosfolipídeos/química , Fosfolipídeos/metabolismo , Psoríase/imunologia , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/fisiologia , Receptores de Antígenos de Linfócitos T alfa-beta/química , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T/imunologiaRESUMO
CD1 proteins present microbial lipids to T cells. Germline-encoded mycolyl lipid-reactive (GEM) T cells with conserved αß 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 ß-chains as tweezers to surround and grip the glucose moiety of GMM, GEM TCRs create a highly specific mechanism for recognizing this mycobacterial glycolipid.
Assuntos
Antígenos CD1/metabolismo , Glicolipídeos/imunologia , Tuberculose Latente/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Antígenos de Histocompatibilidade Menor/metabolismo , Mycobacterium phlei , Conformação Proteica , Rhodococcus equiRESUMO
Galectins are an evolutionarily conserved family of proteins that translate glycan recognition into cellular effects. Galectin-11 is a unique member of the galectin family that is only expressed in ruminants such as sheep, goat and cattle and that plays a critical role in several important biological processes, such as reproduction and parasite-mediated innate immune responses. Currently, these two areas are of major importance for the sustainability of ruminant livestock production. Despite the emerging biological significance of galectin-11, no structural information is available. It is expected that structural studies will unravel the functional mechanisms of galectin-11 activity. Here, the expression, purification and crystallization of the ruminant-specific galectin-11 from domestic sheep and the collection of X-ray data to 2.0â Å resolution are reported.