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1
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Thio CLP, Shao JS, Luo CH, Chang YJ. Decoding innate lymphoid cells and innate-like lymphocytes in asthma: pathways to mechanisms and therapies. J Biomed Sci 2025; 32:48. [PMID: 40355861 PMCID: PMC12067961 DOI: 10.1186/s12929-025-01142-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Accepted: 04/29/2025] [Indexed: 05/15/2025] Open
Abstract
Asthma is a chronic inflammatory lung disease driven by a complex interplay between innate and adaptive immune components. Among these, innate lymphoid cells (ILCs) and innate-like lymphocytes have emerged as crucial players in shaping the disease phenotype. Within the ILC family, group 2 ILCs (ILC2s), in particular, contribute significantly to type 2 inflammation through their rapid production of cytokines such as IL-5 and IL-13, promoting airway eosinophilia and airway hyperreactivity. On the other hand, innate-like lymphocytes such as invariant natural killer T (iNKT) cells can play either pathogenic or protective roles in asthma, depending on the stimuli and lung microenvironment. Regulatory mechanisms, including cytokine signaling, metabolic and dietary cues, and interactions with other immune cells, play critical roles in modulating their functions. In this review, we highlight current findings on the role of ILCs and innate-like lymphocytes in asthma development and pathogenesis. We also examine the underlying mechanisms regulating their function and their interplay with other immune cells. Finally, we explore current therapies targeting these cells and their effector cytokines for asthma management.
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Affiliation(s)
- Christina Li-Ping Thio
- Institute of Biomedical Sciences, Academia Sinica, No. 128 Academia Road, Section 2, Nankang, Taipei City, 115, Taiwan
| | - Jheng-Syuan Shao
- Institute of Biomedical Sciences, Academia Sinica, No. 128 Academia Road, Section 2, Nankang, Taipei City, 115, Taiwan
- Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei City, 115, Taiwan
| | - Chia-Hui Luo
- Institute of Biomedical Sciences, Academia Sinica, No. 128 Academia Road, Section 2, Nankang, Taipei City, 115, Taiwan
- Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei City, 115, Taiwan
| | - Ya-Jen Chang
- Institute of Biomedical Sciences, Academia Sinica, No. 128 Academia Road, Section 2, Nankang, Taipei City, 115, Taiwan.
- Institute of Translational Medicine and New Drug Development, China Medical University, Taichung City, 404, Taiwan.
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2
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Chatterjee P, Brahma S, Cresswell P, Bandyopadhyay S. CD1d-iNKT Axis in Infectious Diseases: Lessons Learned From the Past. Scand J Immunol 2025; 101:e70024. [PMID: 40243400 DOI: 10.1111/sji.70024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Revised: 03/27/2025] [Accepted: 04/04/2025] [Indexed: 04/18/2025]
Abstract
CD1d is an antigen-presenting molecule that presents lipid or glycolipid antigens to iNKT cells, a distinct subset of T lymphocytes characterised by their innate-like properties and restricted use of Vα, Jα and Vβ segments. The CD1d-iNKT axis represents an interesting aspect of the immune system with significant potential for therapeutic interventions against infectious diseases. Upon recognition of lipid antigens, iNKT cells initiate rapid and potent immune responses, releasing a diverse array of cytokines such as IL-4, IL-13, IFN-γ etc. that profoundly influence immune reactions against various pathogens, including bacteria and parasites, bridging innate and adaptive immunity. We identify and describe the key features of lipidic antigens and their derivatives that determine the nature of their antigenicity. Furthermore, modulating CD1d-driven iNKT cell responses by an array of lipid and glycolipid antigens holds promise as adjunctive therapy to existing antimicrobial treatments. Understanding the complexities of the CD1d-iNKT axis and exploiting its therapeutic potential in the case of infectious diseases could lead to innovative immunotherapeutic strategies, ushering in a new era of immunotherapy against pathogenic insults.
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Affiliation(s)
- Priyajit Chatterjee
- University Science Instrument Centre, The University of Burdwan, Burdwan, West Bengal, India
| | - Shubhranil Brahma
- Department of Zoology, Iswar Chandra Vidyasagar College, Belonia, South Tripura, Tripura, India
| | - Peter Cresswell
- Yale University School of Medicine, New Haven, Connecticut, USA
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3
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Liu R, Zhang J, Chen S, Xiao Y, Hu J, Zhou Z, Xie L. Intestinal mucosal immunity and type 1 diabetes: Non-negligible communication between gut and pancreas. Diabetes Obes Metab 2025; 27:1045-1064. [PMID: 39618164 PMCID: PMC11802406 DOI: 10.1111/dom.16101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 11/16/2024] [Accepted: 11/18/2024] [Indexed: 02/08/2025]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by T cell-mediated pancreatic β cell loss, resulting in lifelong absolute insulin deficiency and hyperglycaemia. Environmental factors are recognized as a key contributor to the development of T1D, with the gut serving as a primary interface for environmental stimuli. Recent studies have revealed that the alterations in the intestinal microenvironment profoundly affect host immune responses, contributing to the aetiology and pathogenesis of T1D. However, the dominant intestinal immune cells and the underlying mechanisms remain incompletely elucidated. In this review, we provide an overview of the possible mechanisms of the intestinal mucosal system that underpin the pathogenesis of T1D, shedding light on the roles of both non-classical and classical immune cells in T1D. Our goal is to gain insights into how modulating these immune components may hold potential implications for T1D prevention and provide novel perspectives for immune-mediated therapy.
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Affiliation(s)
- Ruonan Liu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Jing Zhang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Si Chen
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life ScienceHunan Normal UniversityChangshaChina
| | - Yang Xiao
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Jingyi Hu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Lingxiang Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
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4
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Pinheiro L, Freitas M, Branco PS. Phosphate-Containing Glycolipids: A Review on Synthesis and Bioactivity. ChemMedChem 2024; 19:e202400315. [PMID: 39031174 DOI: 10.1002/cmdc.202400315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 07/18/2024] [Accepted: 07/18/2024] [Indexed: 07/22/2024]
Abstract
Phosphate-containing glycolipids (PcGL) are scarcer than the better understood glycolipids. They are composed of arrangements of phosphate, carbohydrates and glycerol units and are always found associated with lipids. PcGL are often found associated with cell membranes, suggesting they play roles in cell membrane structure and intercellular interactions. This article aims to provide an up-to-date overview of the existing knowledge and research on PcGL, emphasizing their synthesis and wide range of biological activities. When it comes to the synthesis of PcGL compounds, the strategies for glycosylation mainly rely on the thioglycoside donor, the trichloroacetamidate donor and halide donor strategies, while phosphorylation is stapled and falls on either phosphite chemistry or phosphoryl chloride chemistry. Certain bacteria utilize PcGLs in their pathogenicity, triggering an inflammatory response within the host's defense mechanisms. The best-known examples of these structures are teichoic acids, lipopolysaccharide and the capsular polysaccharide found in bacteria, all of which are frequently implicated in bacterial infections. Given the degree of variability within PcGL structures, they were found to display a wide range of bioactivities. PcGL compounds were found to: (1) have anti-metastatic properties, (2) behave as agonists or antagonists of platelet aggregation, (3) be mostly pro-inflammatory, (4) display antifungal and antibiotic activity and (5) have neurogenic activity.
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Affiliation(s)
- Luís Pinheiro
- Department of Chemistry, NOVA School of Science and Technology, LAQV-REQUIMTE, Campus da Caparica, 2825-149, Caparica, Portugal
| | - Marisa Freitas
- Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, LAQV-REQUIMTE, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal
| | - Paula S Branco
- Department of Chemistry, NOVA School of Science and Technology, LAQV-REQUIMTE, Campus da Caparica, 2825-149, Caparica, Portugal
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5
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Samer C, McWilliam HEG, McSharry BP, Burchfield JG, Stanton RJ, Rossjohn J, Villadangos JA, Abendroth A, Slobedman B. Impaired endocytosis and accumulation in early endosomal compartments defines herpes simplex virus-mediated disruption of the nonclassical MHC class I-related molecule MR1. J Biol Chem 2024; 300:107748. [PMID: 39260697 PMCID: PMC11736056 DOI: 10.1016/j.jbc.2024.107748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 08/13/2024] [Accepted: 08/21/2024] [Indexed: 09/13/2024] Open
Abstract
Presentation of metabolites by the major histocompatibility complex class I-related protein 1 (MR1) molecule to mucosal-associated invariant T cells is impaired during herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections. This is surprising given these viruses do not directly synthesise MR1 ligands. We have previously identified several HSV proteins responsible for rapidly downregulating the intracellular pool of immature MR1, effectively inhibiting new surface antigen presentation, while preexisting ligand-bound mature MR1 is unexpectedly upregulated by HSV-1. Using flow cytometry, immunoblotting, and high-throughput fluorescence microscopy, we demonstrate that the endocytosis of surface MR1 is impaired during HSV infection and that internalized molecules accumulate in EEA1-labeled early endosomes, avoiding degradation. We establish that the short MR1 cytoplasmic tail is not required for HSV-1-mediated downregulation of immature molecules; however it may play a role in the retention of mature molecules on the surface and in early endosomes. We also determine that the HSV-1 US3 protein, the shorter US3.5 kinase and the full-length HSV-2 homolog, all predominantly target mature surface rather than total MR1 levels. We propose that the downregulation of intracellular and cell surface MR1 molecules by US3 and other HSV proteins is an immune-evasive countermeasure to minimize the effect of impaired MR1 endocytosis, which might otherwise render infected cells susceptible to MR1-mediated killing by mucosal-associated invariant T cells.
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Affiliation(s)
- Carolyn Samer
- Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, and the Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia
| | - Hamish E G McWilliam
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia
| | - Brian P McSharry
- Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, and the Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia; School of Dentistry and Medical Sciences, Faculty of Science and Health, and Gulbali Institute, Charles Sturt University, Wagga Wagga, New South Wales, Australia
| | - James G Burchfield
- Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia; School of Life and Environmental Sciences, The University of Sydney, Camperdown, New South Wales, Australia
| | - Richard J Stanton
- Division of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, Wales, UK
| | - Jamie Rossjohn
- Division of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, Wales, UK; Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Jose A Villadangos
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia; Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
| | - Allison Abendroth
- Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, and the Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia
| | - Barry Slobedman
- Infection, Immunity and Inflammation, School of Medical Sciences, Faculty of Medicine and Health, and the Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia.
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6
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Cao TP, Shahine A, Cox LR, Besra GS, Moody DB, Rossjohn J. A structural perspective of how T cell receptors recognize the CD1 family of lipid antigen-presenting molecules. J Biol Chem 2024; 300:107511. [PMID: 38945451 PMCID: PMC11780374 DOI: 10.1016/j.jbc.2024.107511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 06/21/2024] [Accepted: 06/24/2024] [Indexed: 07/02/2024] Open
Abstract
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.
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Affiliation(s)
- Thinh-Phat Cao
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Victoria, Australia
| | - Adam Shahine
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Victoria, Australia
| | - Liam R Cox
- School of Chemistry, University of Birmingham, Birmingham, United Kingdom
| | - Gurdyal S Besra
- Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Birmingham, UK
| | - D Branch Moody
- Division of Rheumatology, Inflammation and Immunity, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Jamie Rossjohn
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Victoria, Australia; Institute of Infection and Immunity, Cardiff University, School of Medicine, Cardiff, UK.
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7
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Jeong D, Woo YD, Chung DH. Invariant natural killer T cells in lung diseases. Exp Mol Med 2023; 55:1885-1894. [PMID: 37696892 PMCID: PMC10545712 DOI: 10.1038/s12276-023-01024-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 04/12/2023] [Indexed: 09/13/2023] Open
Abstract
Invariant natural killer T (iNKT) cells are a subset of T cells that are characterized by a restricted T-cell receptor (TCR) repertoire and a unique ability to recognize glycolipid antigens. These cells are found in all tissues, and evidence to date suggests that they play many immunological roles in both homeostasis and inflammatory conditions. The latter include lung inflammatory diseases such as asthma and infections: the roles of lung-resident iNKT cells in these diseases have been extensively researched. Here, we provide insights into the biology of iNKT cells in health and disease, with a particular focus on the role of pulmonary iNKT cells in airway inflammation and other lung diseases.
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Affiliation(s)
- Dongjin Jeong
- Laboratory of Immune Regulation in Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Yeon Duk Woo
- Laboratory of Immune Regulation in Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Doo Hyun Chung
- Laboratory of Immune Regulation in Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
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8
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Kim S, Cho S, Kim JH. CD1-mediated immune responses in mucosal tissues: molecular mechanisms underlying lipid antigen presentation system. Exp Mol Med 2023; 55:1858-1871. [PMID: 37696897 PMCID: PMC10545705 DOI: 10.1038/s12276-023-01053-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 05/02/2023] [Accepted: 05/07/2023] [Indexed: 09/13/2023] Open
Abstract
The cluster of differentiation 1 (CD1) molecule differs from major histocompatibility complex class I and II because it presents glycolipid/lipid antigens. Moreover, the CD1-restricted T cells that recognize these self and foreign antigens participate in both innate and adaptive immune responses. CD1s are constitutively expressed by professional and nonprofessional antigen-presenting cells in mucosal tissues, namely, the skin, lung, and intestine. This suggests that CD1-reactive T cells are involved in the immune responses of these tissues. Indeed, evidence suggests that these cells play important roles in diverse diseases, such as inflammation, autoimmune disease, and infection. Recent studies elucidating the molecular mechanisms by which CD1 presents lipid antigens suggest that defects in these mechanisms could contribute to the activities of CD1-reactive T cells. Thus, improving our understanding of these mechanisms could lead to new and effective therapeutic approaches to CD1-associated diseases. In this review, we discuss the CD1-mediated antigen presentation system and its roles in mucosal tissue immunity.
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Affiliation(s)
- Seohyun Kim
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Sumin Cho
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Ji Hyung Kim
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
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9
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Iwanami N, Richter AS, Sikora K, Boehm T. Tnpo3 controls splicing of the pre-mRNA encoding the canonical TCR α chain of iNKT cells. Nat Commun 2023; 14:3645. [PMID: 37339974 DOI: 10.1038/s41467-023-39422-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 06/13/2023] [Indexed: 06/22/2023] Open
Abstract
Unconventional T cells, such as innate natural killer T cells (iNKT) cells, are an important part of vertebrate immune defences. iNKT recognise glycolipids through a T cell receptor (TCR) that is composed of a semi-invariant TCR α chain, paired with a restricted set of TCR β chains. Here, we show that splicing of the cognate Trav11-Traj18-Trac pre-mRNA encoding the characteristic Vα14Jα18 variable region of this semi-invariant TCR depends on the presence of Tnpo3. The Tnpo3 gene encodes a nuclear transporter of the β-karyopherin family whose cargo includes various splice regulators. The block of iNKT cell development in the absence of Tnpo3 can be overcome by transgenic provision of a rearranged Trav11-Traj18-Trac cDNA, indicating that Tnpo3 deficiency does not interfere with the development of iNKT cells per se. Our study thus identifies a role for Tnpo3 in regulating the splicing of the pre-mRNA encoding the cognate TCRα chain of iNKT cells.
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Affiliation(s)
- Norimasa Iwanami
- Department of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
- Center for Bioscience Research and Education, Utsunomiya University, Utsunomiya, Tochigi, 321-8505, Japan
| | - Andreas S Richter
- Bioinformatics Unit, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
- Genedata AG, Margarethenstrasse 38, 4053, Basel, Switzerland
| | - Katarzyna Sikora
- Bioinformatics Unit, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Thomas Boehm
- Bioinformatics Unit, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
- Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany.
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10
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Witt KD. Role of MHC class I pathways in Mycobacterium tuberculosis antigen presentation. Front Cell Infect Microbiol 2023; 13:1107884. [PMID: 37009503 PMCID: PMC10050577 DOI: 10.3389/fcimb.2023.1107884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 02/23/2023] [Indexed: 03/17/2023] Open
Abstract
MHC class I antigen processing is an underappreciated area of nonviral host–pathogen interactions, bridging both immunology and cell biology, where the pathogen’s natural life cycle involves little presence in the cytoplasm. The effective response to MHC-I foreign antigen presentation is not only cell death but also phenotypic changes in other cells and stimulation of the memory cells ready for the next antigen reoccurrence. This review looks at the MHC-I antigen processing pathway and potential alternative sources of the antigens, focusing on Mycobacterium tuberculosis (Mtb) as an intracellular pathogen that co-evolved with humans and developed an array of decoy strategies to survive in a hostile environment by manipulating host immunity to its own advantage. As that happens via the selective antigen presentation process, reinforcement of the effective antigen recognition on MHC-I molecules may stimulate subsets of effector cells that act earlier and more locally. Vaccines against tuberculosis (TB) could potentially eliminate this disease, yet their development has been slow, and success is limited in the context of this global disease’s spread. This review’s conclusions set out potential directions for MHC-I-focused approaches for the next generation of vaccines.
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Affiliation(s)
- Karolina D. Witt
- Pandemic Sciences Institute, University of Oxford, Oxford, United Kingdom
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- *Correspondence: Karolina D. Witt,
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11
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Kim H, Shin SJ. Pathological and protective roles of dendritic cells in Mycobacterium tuberculosis infection: Interaction between host immune responses and pathogen evasion. Front Cell Infect Microbiol 2022; 12:891878. [PMID: 35967869 PMCID: PMC9366614 DOI: 10.3389/fcimb.2022.891878] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
Dendritic cells (DCs) are principal defense components that play multifactorial roles in translating innate immune responses to adaptive immunity in Mycobacterium tuberculosis (Mtb) infections. The heterogeneous nature of DC subsets follows their altered functions by interacting with other immune cells, Mtb, and its products, enhancing host defense mechanisms or facilitating pathogen evasion. Thus, a better understanding of the immune responses initiated, promoted, and amplified or inhibited by DCs in Mtb infection is an essential step in developing anti-tuberculosis (TB) control measures, such as host-directed adjunctive therapy and anti-TB vaccines. This review summarizes the recent advances in salient DC subsets, including their phenotypic classification, cytokine profiles, functional alterations according to disease stages and environments, and consequent TB outcomes. A comprehensive overview of the role of DCs from various perspectives enables a deeper understanding of TB pathogenesis and could be useful in developing DC-based vaccines and immunotherapies.
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12
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Pramanik A, Bhattacharyya S. Myeloid derived suppressor cells and innate immune system interaction in tumor microenvironment. Life Sci 2022; 305:120755. [PMID: 35780842 DOI: 10.1016/j.lfs.2022.120755] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 06/23/2022] [Accepted: 06/27/2022] [Indexed: 12/24/2022]
Abstract
The tumor microenvironment is a complex domain that not only contains tumor cells but also a plethora of other host immune cells. By nature, the tumor microenvironment is a highly immunosuppressive milieu providing growing conditions for tumor cells. A major immune cell population that contributes most in the development of this immunosuppressive microenvironment is the MDSC, a heterogenous population of immature cells. Although found in small numbers only in the bone marrow of healthy individuals, they readily migrate to the lymph nodes and tumor site during cancer pathogenesis. MDSC mediated disruption of antitumor T cell activity is a major cause of the immunosuppression at the tumor site, but recent findings have shown that MDSC mediated dysfunction of other major immune cells might also play an important role. In this article we will review how crosstalk with MDSC alters the activity of both conventional and unconventional immune cells that inhibits the antitumor immunity and promotes cancer progression.
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Affiliation(s)
- Anik Pramanik
- Immunobiology and Translational Medicine Laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia 723104, West Bengal, India
| | - Sankar Bhattacharyya
- Immunobiology and Translational Medicine Laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia 723104, West Bengal, India.
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13
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Silva CS, Sundling C, Folkesson E, Fröberg G, Nobrega C, Canto-Gomes J, Chambers BJ, Lakshmikanth T, Brodin P, Bruchfeld J, Nigou J, Correia-Neves M, Källenius G. High Dimensional Immune Profiling Reveals Different Response Patterns in Active and Latent Tuberculosis Following Stimulation With Mycobacterial Glycolipids. Front Immunol 2021; 12:727300. [PMID: 34887849 PMCID: PMC8650708 DOI: 10.3389/fimmu.2021.727300] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 10/18/2021] [Indexed: 11/13/2022] Open
Abstract
Upon infection with Mycobacterium tuberculosis (Mtb) the host immune response might clear the bacteria, control its growth leading to latent tuberculosis (LTB), or fail to control its growth resulting in active TB (ATB). There is however no clear understanding of the features underlying a more or less effective response. Mtb glycolipids are abundant in the bacterial cell envelope and modulate the immune response to Mtb, but the patterns of response to glycolipids are still underexplored. To identify the CD45+ leukocyte activation landscape induced by Mtb glycolipids in peripheral blood of ATB and LTB, we performed a detailed assessment of the immune response of PBMCs to the Mtb glycolipids lipoarabinomannan (LAM) and its biosynthetic precursor phosphatidyl-inositol mannoside (PIM), and purified-protein derivate (PPD). At 24 h of stimulation, cell profiling and secretome analysis was done using mass cytometry and high-multiplex immunoassay. PIM induced a diverse cytokine response, mainly affecting antigen-presenting cells to produce both pro-inflammatory and anti-inflammatory cytokines, but not IFN-γ, contrasting with PPD that was a strong inducer of IFN-γ. The effect of PIM on the antigen-presenting cells was partly TLR2-dependent. Expansion of monocyte subsets in response to PIM or LAM was reduced primarily in LTB as compared to healthy controls, suggesting a hyporesponsive/tolerance pattern derived from Mtb infection.
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Affiliation(s)
- Carolina S Silva
- Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's, PT Government Associate Laboratory, Braga, Portugal
| | - Christopher Sundling
- Division of Infectious Diseases, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Elin Folkesson
- Division of Infectious Diseases, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Gabrielle Fröberg
- Division of Infectious Diseases, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Claudia Nobrega
- Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's, PT Government Associate Laboratory, Braga, Portugal
| | - João Canto-Gomes
- Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's, PT Government Associate Laboratory, Braga, Portugal
| | - Benedict J Chambers
- Center for Infectious Medicine, Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Tadepally Lakshmikanth
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Petter Brodin
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
| | - Judith Bruchfeld
- Division of Infectious Diseases, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Jérôme Nigou
- Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), Université Paul Sabatier, Toulouse, France
| | - Margarida Correia-Neves
- Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's, PT Government Associate Laboratory, Braga, Portugal.,Division of Infectious Diseases, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Gunilla Källenius
- Division of Infectious Diseases, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
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14
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Vogt S, Mattner J. NKT Cells Contribute to the Control of Microbial Infections. Front Cell Infect Microbiol 2021; 11:718350. [PMID: 34595131 PMCID: PMC8477047 DOI: 10.3389/fcimb.2021.718350] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/25/2021] [Indexed: 12/14/2022] Open
Abstract
Innate (-like) T lymphocytes such as natural killer T (NKT) cells play a pivotal role in the recognition of microbial infections and their subsequent elimination. They frequently localize to potential sites of pathogen entry at which they survey extracellular and intracellular tissue spaces for microbial antigens. Engagement of their T cell receptors (TCRs) induces an explosive release of different cytokines and chemokines, which often pre-exist as constitutively expressed gene transcripts in NKT cells and underlie their poised effector state. Thus, NKT cells regulate immune cell migration and activation and subsequently, bridge innate and adaptive immune responses. In contrast to conventional T cells, which react to peptide antigens, NKT cells recognize lipids presented by the MHC class I like CD1d molecule on antigen presenting cells (APCs). Furthermore, each NKT cell TCR can recognize various antigen specificities, whereas a conventional T lymphocyte TCR reacts mostly only to one single antigen. These lipid antigens are either intermediates of the intracellular APC`s-own metabolism or originate from the cell wall of different bacteria, fungi or protozoan parasites. The best-characterized subset, the type 1 NKT cell subset expresses a semi-invariant TCR. In contrast, the TCR repertoire of type 2 NKT cells is diverse. Furthermore, NKT cells express a panoply of inhibitory and activating NK cell receptors (NKRs) that contribute to their primarily TCR-mediated rapid, innate like immune activation and even allow an adaption of their immune response in an adoptive like manner. Dueto their primary localization at host-environment interfaces, NKT cells are one of the first immune cells that interact with signals from different microbial pathogens. Vice versa, the mutual exchange with local commensal microbiota shapes also the biology of NKT cells, predominantly in the gastrointestinal tract. Following infection, two main signals drive the activation of NKT cells: first, cognate activation upon TCR ligation by microbial or endogenous lipid antigens; and second, bystander activation due to cytokines. Here we will discuss the role of NKT cells in the control of different microbial infections comparing pathogens expressing lipid ligands in their cell walls to infectious agents inducing endogenous lipid antigen presentation by APCs.
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Affiliation(s)
- Stefan Vogt
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Jochen Mattner
- Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, Erlangen, Germany
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15
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Gálvez NMS, Bohmwald K, Pacheco GA, Andrade CA, Carreño LJ, Kalergis AM. Type I Natural Killer T Cells as Key Regulators of the Immune Response to Infectious Diseases. Clin Microbiol Rev 2021; 34:e00232-20. [PMID: 33361143 PMCID: PMC7950362 DOI: 10.1128/cmr.00232-20] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The immune system must work in an orchestrated way to achieve an optimal response upon detection of antigens. The cells comprising the immune response are traditionally divided into two major subsets, innate and adaptive, with particular characteristics for each type. Type I natural killer T (iNKT) cells are defined as innate-like T cells sharing features with both traditional adaptive and innate cells, such as the expression of an invariant T cell receptor (TCR) and several NK receptors. The invariant TCR in iNKT cells interacts with CD1d, a major histocompatibility complex class I (MHC-I)-like molecule. CD1d can bind and present antigens of lipid nature and induce the activation of iNKT cells, leading to the secretion of various cytokines, such as gamma interferon (IFN-γ) and interleukin 4 (IL-4). These cytokines will aid in the activation of other immune cells following stimulation of iNKT cells. Several molecules with the capacity to bind to CD1d have been discovered, including α-galactosylceramide. Likewise, several molecules have been synthesized that are capable of polarizing iNKT cells into different profiles, either pro- or anti-inflammatory. This versatility allows NKT cells to either aid or impair the clearance of pathogens or to even control or increase the symptoms associated with pathogenic infections. Such diverse contributions of NKT cells to infectious diseases are supported by several publications showing either a beneficial or detrimental role of these cells during diseases. In this article, we discuss current data relative to iNKT cells and their features, with an emphasis on their driving role in diseases produced by pathogenic agents in an organ-oriented fashion.
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Affiliation(s)
- Nicolás M S Gálvez
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Karen Bohmwald
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gaspar A Pacheco
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Catalina A Andrade
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Leandro J Carreño
- Millennium Institute on Immunology and Immunotherapy, Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Alexis M Kalergis
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
- Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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16
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Walker NF, Opondo C, Meintjes G, Jhilmeet N, Friedland JS, Elkington PT, Wilkinson RJ, Wilkinson KA. Invariant Natural Killer T-cell Dynamics in Human Immunodeficiency Virus-associated Tuberculosis. Clin Infect Dis 2021; 70:1865-1874. [PMID: 31190065 PMCID: PMC7156773 DOI: 10.1093/cid/ciz501] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 06/11/2019] [Indexed: 01/04/2023] Open
Abstract
Background Tuberculosis (TB) is the leading cause of mortality and morbidity in people living with human immunodeficiency virus (HIV) infection (PLWH). PLWH with TB disease are at risk of the paradoxical TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) when they commence antiretroviral therapy. However, the pathophysiology is incompletely understood and specific therapy is lacking. We investigated the hypothesis that invariant natural killer T (iNKT) cells contribute to innate immune dysfunction associated with TB-IRIS. Methods In a cross-sectional study of 101 PLWH and HIV-uninfected South African patients with active TB and controls, iNKT cells were enumerated using α-galactosylceramide-loaded CD1d tetramers and subsequently functionally characterized by flow cytometry. In a second study of 49 people with HIV type 1 (HIV-1) and active TB commencing antiretroviral therapy, iNKT cells in TB-IRIS patients and non-IRIS controls were compared longitudinally. Results Circulating iNKT cells were reduced in HIV-1 infection, most significantly the CD4+ subset, which was inversely associated with HIV-1 viral load. iNKT cells in HIV-associated TB had increased surface CD107a expression, indicating cytotoxic degranulation. Relatively increased iNKT cell frequency in patients with HIV-1 infection and active TB was associated with development of TB-IRIS following antiretroviral therapy initiation. iNKT cells in TB-IRIS were CD4+CD8– subset depleted and degranulated around the time of TB-IRIS onset. Conclusions Reduced iNKT cell CD4+ subsets as a result of HIV-1 infection may skew iNKT cell functionality toward cytotoxicity. Increased CD4– cytotoxic iNKT cells may contribute to immunopathology in TB-IRIS.
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Affiliation(s)
- Naomi F Walker
- Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, South Africa.,Infectious Diseases and Immunity, and Imperial College Wellcome Trust Centre for Global Health, Imperial College London, United Kingdom.,Department of Medicine, University of Cape Town, Observatory, South Africa.,Tuberculosis Centre and Department of Clinical Research
| | - Charles Opondo
- Department of Medical Statistics, London School of Hygiene and Tropical Medicine
| | - Graeme Meintjes
- Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, South Africa.,Department of Medicine, University of Cape Town, Observatory, South Africa
| | - Nishtha Jhilmeet
- Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, South Africa
| | - Jon S Friedland
- Institute of Infection and Immunity, St George's, University of London
| | - Paul T Elkington
- Infectious Diseases and Immunity, and Imperial College Wellcome Trust Centre for Global Health, Imperial College London, United Kingdom.,National Institute for Health Research Biomedical Research Centre, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton
| | - Robert J Wilkinson
- Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, South Africa.,Department of Medicine, University of Cape Town, Observatory, South Africa.,Francis Crick Institute, London.,Department of Medicine, Imperial College London, United Kingdom
| | - Katalin A Wilkinson
- Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, South Africa.,Department of Medicine, University of Cape Town, Observatory, South Africa.,Francis Crick Institute, London
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17
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The thick waxy coat of mycobacteria, a protective layer against antibiotics and the host's immune system. Biochem J 2020; 477:1983-2006. [PMID: 32470138 PMCID: PMC7261415 DOI: 10.1042/bcj20200194] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 04/30/2020] [Accepted: 05/04/2020] [Indexed: 12/22/2022]
Abstract
Tuberculosis, caused by the pathogenic bacterium Mycobacterium tuberculosis (Mtb), is the leading cause of death from an infectious disease, with a mortality rate of over a million people per year. This pathogen's remarkable resilience and infectivity is largely due to its unique waxy cell envelope, 40% of which comprises complex lipids. Therefore, an understanding of the structure and function of the cell wall lipids is of huge indirect clinical significance. This review provides a synopsis of the cell envelope and the major lipids contained within, including structure, biosynthesis and roles in pathogenesis.
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18
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Zhao SY, Li N, Luo WY, Zhang NN, Zhou RY, Li CY, Wang J. Chemical synthesis and antigenic activity of a phosphatidylinositol mannoside epitope from Mycobacterium tuberculosis. Chem Commun (Camb) 2020; 56:14067-14070. [PMID: 33104149 DOI: 10.1039/d0cc05573e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Phosphatidylinositol mannosides (PIMs) have been investigated as lipidic antigens for a new subunit tuberculosis vaccine. A non-natural diacylated phosphatidylinositol mannoside (Ac2PIM2) was designed and synthesized by mimicking the natural PIM6 processing procedure in dentritic cells. This synthetic Ac2PIM2 was achieved from α-methyl d-glucopyranoside 1 in 17 steps in 2.5% overall yield. A key feature of the strategy was extending the use of the chiral myo-inositol building block A to the O-2 and O-6 positions of the inositol unit to allow for introducing the mannose building blocks B1 and B2, and to the O-1 position for the phosphoglycerol building block C. Building block A, being a flexible core unit, may facilitate future access to other higher-order PIM analogues. A preliminary antigenic study showed that the synthetic PIM epitope (Ac2PIM2) was significantly more active than natural Ac2PIM2, which indicated that the synthetic Ac2PIM2 can be strongly immunoactive and may be developed as a potential vaccine.
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Affiliation(s)
- Shi-Yuan Zhao
- School of Pharmacy, Yancheng Teachers University, Hope Avenue South Road No. 2, Yancheng, 224007, Jiangsu Province, P. R. China.
| | - Na Li
- School of Pharmacy, Yancheng Teachers University, Hope Avenue South Road No. 2, Yancheng, 224007, Jiangsu Province, P. R. China.
| | - Wan-Yue Luo
- School of Pharmacy, Yancheng Teachers University, Hope Avenue South Road No. 2, Yancheng, 224007, Jiangsu Province, P. R. China.
| | - Nan-Nan Zhang
- School of Pharmacy, Yancheng Teachers University, Hope Avenue South Road No. 2, Yancheng, 224007, Jiangsu Province, P. R. China.
| | - Rong-Ye Zhou
- School of Pharmacy, Yancheng Teachers University, Hope Avenue South Road No. 2, Yancheng, 224007, Jiangsu Province, P. R. China.
| | - Chen-Yu Li
- School of Pharmacy, Yancheng Teachers University, Hope Avenue South Road No. 2, Yancheng, 224007, Jiangsu Province, P. R. China.
| | - Jin Wang
- School of Pharmacy, Yancheng Teachers University, Hope Avenue South Road No. 2, Yancheng, 224007, Jiangsu Province, P. R. China. and Université de Toulouse, Université Toulouse III - Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex 9, France and CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), 205 route de Narbonne, 31077 Toulouse, France
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19
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Lin Q, Kuypers M, Philpott DJ, Mallevaey T. The dialogue between unconventional T cells and the microbiota. Mucosal Immunol 2020; 13:867-876. [PMID: 32704035 DOI: 10.1038/s41385-020-0326-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 06/19/2020] [Accepted: 06/19/2020] [Indexed: 02/04/2023]
Abstract
The mammalian immune system is equipped with unconventional T cells that respond to microbial molecules such as glycolipids and small-molecule metabolites, which are invisible to conventional CD4 and CD8 T cells. Unconventional T cells include invariant natural killer T (iNKT) cells and mucosa-associated invariant T (MAIT) cells, which are involved in a wide range of infectious and non-infectious diseases, such as cancer and autoimmunity. In addition, their high conservation across mammals, their restriction by non-polymorphic antigen-presenting molecules, and their immediate and robust responses make these 'innate' T cells appealing targets for the development of one-size-fits-all immunotherapies. In this review, we discuss how iNKT and MAIT cells directly and indirectly detect the presence of and respond to pathogenic and commensal microbes. We also explore the current understanding of the bidirectional relationship between the microbiota and innate T cells, and how this crosstalk shapes the immune response in disease.
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Affiliation(s)
- Qiaochu Lin
- Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Meggie Kuypers
- Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Dana J Philpott
- Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Thierry Mallevaey
- Department of Immunology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. .,Institute of Biomedical Engineering, University of Toronto, 164 College Street, Toronto, ON, M5S 3G9, Canada.
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20
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Driver JP, de Carvalho Madrid DM, Gu W, Artiaga BL, Richt JA. Modulation of Immune Responses to Influenza A Virus Vaccines by Natural Killer T Cells. Front Immunol 2020; 11:2172. [PMID: 33193296 PMCID: PMC7606973 DOI: 10.3389/fimmu.2020.02172] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 08/10/2020] [Indexed: 12/20/2022] Open
Abstract
Influenza A viruses (IAVs) circulate widely among different mammalian and avian hosts and sometimes give rise to zoonotic infections. Vaccination is a mainstay of IAV prevention and control. However, the efficacy of IAV vaccines is often suboptimal because of insufficient cross-protection among different IAV genotypes and subtypes as well as the inability to keep up with the rapid molecular evolution of IAV strains. Much attention is focused on improving IAV vaccine efficiency using adjuvants, which are substances that can modulate and enhance immune responses to co-administered antigens. The current review is focused on a non-traditional approach of adjuvanting IAV vaccines by therapeutically targeting the immunomodulatory functions of a rare population of innate-like T lymphocytes called invariant natural killer T (iNKT) cells. These cells bridge the innate and adaptive immune systems and are capable of stimulating a wide array of immune cells that enhance vaccine-mediated immune responses. Here we discuss the factors that influence the adjuvant effects of iNKT cells for influenza vaccines as well as the obstacles that must be overcome before this novel adjuvant approach can be considered for human or veterinary use.
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Affiliation(s)
- John P Driver
- Department of Animal Sciences, University of Florida, Gainesville, FL, United States
| | | | - Weihong Gu
- Department of Animal Sciences, University of Florida, Gainesville, FL, United States
| | - Bianca L Artiaga
- Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, United States
| | - Jürgen A Richt
- Diagnostic Medicine/Pathobiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS, United States
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21
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Shepherd FR, McLaren JE. T Cell Immunity to Bacterial Pathogens: Mechanisms of Immune Control and Bacterial Evasion. Int J Mol Sci 2020; 21:E6144. [PMID: 32858901 PMCID: PMC7504484 DOI: 10.3390/ijms21176144] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 08/21/2020] [Accepted: 08/24/2020] [Indexed: 02/06/2023] Open
Abstract
The human body frequently encounters harmful bacterial pathogens and employs immune defense mechanisms designed to counteract such pathogenic assault. In the adaptive immune system, major histocompatibility complex (MHC)-restricted αβ T cells, along with unconventional αβ or γδ T cells, respond to bacterial antigens to orchestrate persisting protective immune responses and generate immunological memory. Research in the past ten years accelerated our knowledge of how T cells recognize bacterial antigens and how many bacterial species have evolved mechanisms to evade host antimicrobial immune responses. Such escape mechanisms act to corrupt the crosstalk between innate and adaptive immunity, potentially tipping the balance of host immune responses toward pathological rather than protective. This review examines the latest developments in our knowledge of how T cell immunity responds to bacterial pathogens and evaluates some of the mechanisms that pathogenic bacteria use to evade such T cell immunosurveillance, to promote virulence and survival in the host.
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Affiliation(s)
| | - James E. McLaren
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, UK;
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22
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Anderson CK, Reilly EC, Lee AY, Brossay L. Qa-1-Restricted CD8 + T Cells Can Compensate for the Absence of Conventional T Cells during Viral Infection. Cell Rep 2020; 27:537-548.e5. [PMID: 30970256 PMCID: PMC6472915 DOI: 10.1016/j.celrep.2019.03.059] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 02/18/2019] [Accepted: 03/15/2019] [Indexed: 12/30/2022] Open
Abstract
The role of non-classical T cells during viral infection remains poorly understood. Using the well-established murine model of CMV infection (MCMV) and mice deficient in MHC class Ia molecules, we found that non-classical CD8+ T cells robustly expand after MCMV challenge, become highly activated effectors, and are capable of forming durable memory. Interestingly, although these cells are restricted by MHC class Ib molecules, they respond similarly to conventional T cells. Remarkably, when acting as the sole component of the adaptive immune response, non-classical CD8+ T cells are sufficient to protect against MCMV-induced lethality. We also demonstrate that the MHC class Ib molecule Qa-1 (encoded by H2-T23) restricts a large, and critical, portion of this population. These findings reveal a potential adaptation of the host immune response to compensate for viral evasion of classical T cell immunity. Anderson et al. describe a heterogenous population of non-classical CD8+ T cells responding to MCMV. Importantly, this population can protect mice from MCMV-induced lethality in the absence of other adaptive immune cells. Among the MHC class Ib-restricted CD8+ T cells responding, Qa-1-specific cells are required for protection.
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Affiliation(s)
- Courtney K Anderson
- Department of Molecular Microbiology & Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912, USA
| | - Emma C Reilly
- Department of Molecular Microbiology & Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912, USA
| | - Angus Y Lee
- Cancer Research Laboratory, University of California, Berkeley, Berkeley, CA 94702, USA
| | - Laurent Brossay
- Department of Molecular Microbiology & Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912, USA.
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23
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License to Kill: When iNKT Cells Are Granted the Use of Lethal Cytotoxicity. Int J Mol Sci 2020; 21:ijms21113909. [PMID: 32486268 PMCID: PMC7312231 DOI: 10.3390/ijms21113909] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 05/26/2020] [Accepted: 05/28/2020] [Indexed: 12/13/2022] Open
Abstract
Invariant Natural Killer T (iNKT) cells are a non-conventional, innate-like, T cell population that recognize lipid antigens presented by the cluster of differentiation (CD)1d molecule. Although iNKT cells are mostly known for mediating several immune responses due to their massive and diverse cytokine release, these cells also work as effectors in various contexts thanks to their cytotoxic potential. In this Review, we focused on iNKT cell cytotoxicity; we provide an overview of iNKT cell subsets, their activation cues, the mechanisms of iNKT cell cytotoxicity, the specific roles and outcomes of this activity in various contexts, and how iNKT killing functions are currently activated in cancer immunotherapies. Finally, we discuss the future perspectives for the better understanding and potential uses of iNKT cell killing functions in tumor immunosurveillance.
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24
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Arai Y, Torigoe S, Matsumaru T, Yamasaki S, Fujimoto Y. The key entity of a DCAR agonist, phosphatidylinositol mannoside Ac 1PIM 1: its synthesis and immunomodulatory function. Org Biomol Chem 2020; 18:3659-3663. [PMID: 32356529 DOI: 10.1039/c9ob02724f] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Ac1PIM1 is a potential biosynthetic intermediate for phosphatidylinositol mannosides (PIMs) from Mycobacterium tuberculosis. We achieved the first synthesis of Ac1PIM1 by utilizing an allyl-type protecting group strategy and regioselective phosphorylation of inositol. A very potent agonist of an innate immune receptor DCAR, which is better than previously known agonists, is demonstrated.
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Affiliation(s)
- Yohei Arai
- Faculty of Science and Technology, Keio University. Hiyoshi 3-14-1, Yokohama, Kanagawa 223-8522, Japan.
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25
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Recognition of Mycobacteria by Dendritic Cell Immunoactivating Receptor. Curr Top Microbiol Immunol 2020. [PMID: 32300915 DOI: 10.1007/82_2020_203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2023]
Abstract
Mycobacteria have unique lipids on their cell walls, and the structures and physiological activities of these lipid components have been the subject of many studies. Although the host receptors for mycobacterial lipid have long been elusive, in recent years C-type lectin receptors (CLRs) have been reported to recognize these components. The dendritic cell immunoactivating receptor (DCAR), a CLR member, is encoded by Clec4b1. DCAR, which was identified in 2003, is reported to be associated with the immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptor protein, the Fc receptor γ chain (FcRγ). However, its physiological ligand and biological function were unknown. We recently identified DCAR as an activating receptor for mycobacteria. DCAR recognizes acylated phosphatidyl-inositol mannosides (PIMs) in mycobacteria to promote Th1 responses during mycobacterial infection. This review summarizes recent discoveries about the ligands and immunological roles of DCAR.
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26
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Li Y, Li W, Xie Z, Xu H, He ZG. MpbR, an essential transcriptional factor for Mycobacterium tuberculosis survival in the host, modulates PIM biosynthesis and reduces innate immune responses. J Genet Genomics 2019; 46:575-589. [DOI: 10.1016/j.jgg.2019.12.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 11/28/2019] [Accepted: 12/02/2019] [Indexed: 01/08/2023]
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27
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Vivas W, Leonhardt I, Hünniger K, Häder A, Marolda A, Kurzai O. Multiple Signaling Pathways Involved in Human Dendritic Cell Maturation Are Affected by the Fungal Quorum-Sensing Molecule Farnesol. THE JOURNAL OF IMMUNOLOGY 2019; 203:2959-2969. [DOI: 10.4049/jimmunol.1900431] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 09/25/2019] [Indexed: 01/30/2023]
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28
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Bonam SR, Bhunia D, Muller S, Nerella SG, Alvala M, Halmuthur Mahabalarao SK. Novel trisaccharide based phospholipids as immunomodulators. Int Immunopharmacol 2019; 74:105684. [PMID: 31200340 DOI: 10.1016/j.intimp.2019.105684] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 05/30/2019] [Accepted: 06/04/2019] [Indexed: 12/19/2022]
Abstract
A focused library of novel mannosylated glycophospholipids was synthesized employing imidate coupling and H-phosphate phosphorylation methods. All novel glycophospholipids were evaluated for their receptor interactions by molecular docking studies. Docking studies revealed dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) specific interaction of the glycophospholipid ligand P4 acts, which was further confirmed by in vitro DC-SIGN expression on monocyte-derived dendritic cells (MoDCs). Further, in vitro and in vivo immunomodulatory activity among the six compounds (P1-P6) examined, compound P4 displayed good immunopotentiation and adjuvant properties as indicated by the induced cytokine expression and enhanced ovalbumin (OVA) specific antibody (IgG) titers. Phosphatidylinositol mannosides (PIMs) analogues in the present study enforced the immunomodulatory properties, truncating parent PIMs or tailor-made of PIMs may bring the novel efficacious molecules, which will be useful in vaccine preparation against different diseases.
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Affiliation(s)
- Srinivasa Reddy Bonam
- Vaccine Immunology Laboratory, Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500007, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-IICT Campus, Hyderabad, 500007, India; UMR 7242 CNRS- Neuroimmunology & Peptide Therapy Team, University of Strasbourg, Biotechnology and cell signaling, Illkirch, France/Laboratory of excellence Medalis, Institut de science et d'ingénierie supramoléculaire (ISIS), 67000, Strasbourg, France
| | - Debabrata Bhunia
- Vaccine Immunology Laboratory, Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500007, India
| | - Sylviane Muller
- UMR 7242 CNRS- Neuroimmunology & Peptide Therapy Team, University of Strasbourg, Biotechnology and cell signaling, Illkirch, France/Laboratory of excellence Medalis, Institut de science et d'ingénierie supramoléculaire (ISIS), 67000, Strasbourg, France; University of Strasbourg Institute for Advanced Study (USIAS), 67000 Strasbourg, France
| | - Sridhar Goud Nerella
- Molecular Modeling Facility, Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India
| | - Mallika Alvala
- Molecular Modeling Facility, Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, 500037, India
| | - Sampath Kumar Halmuthur Mahabalarao
- Vaccine Immunology Laboratory, Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, 500007, India; Academy of Scientific and Innovative Research (AcSIR), CSIR-IICT Campus, Hyderabad, 500007, India.
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29
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Burrello C, Pellegrino G, Giuffrè MR, Lovati G, Magagna I, Bertocchi A, Cribiù FM, Boggio F, Botti F, Trombetta E, Porretti L, Di Sabatino A, Vecchi M, Rescigno M, Caprioli F, Facciotti F. Mucosa-associated microbiota drives pathogenic functions in IBD-derived intestinal iNKT cells. Life Sci Alliance 2019; 2:2/1/e201800229. [PMID: 30760554 PMCID: PMC6374994 DOI: 10.26508/lsa.201800229] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 02/01/2019] [Accepted: 02/01/2019] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel disease (IBD) pathogenesis has been linked to the aberrant activation of the Gut-associated lymphoid tissues against components of the intestinal microbiota. Although the contribution of CD4+ T helper cells to inflammatory processes is being increasingly acknowledged, the functional engagement of human invariant natural killer T (iNKT) cells is still poorly defined. Here, we evaluated the functional characteristics of intestinal iNKT cells during IBD pathogenesis and to exploit the role of mucosa-associated microbiota recognition in triggering iNKT cells' pro-inflammatory responses in vivo. Lamina propria iNKT cells, isolated from surgical specimens of active ulcerative colitis and Crohn's disease patients and non-IBD donors, were phenotypically and functionally analyzed ex vivo, and stable cell lines and clones were generated for in vitro functional assays. iNKT cells expressing a pro-inflammatory cytokine profile were enriched in the lamina propria of IBD patients, and their exposure to the mucosa-associated microbiota drives pro-inflammatory activation, inducing direct pathogenic activities against the epithelial barrier integrity. These observations suggest that iNKT cell pro-inflammatory functions may contribute to the fuelling of intestinal inflammation in IBD patients.
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Affiliation(s)
- Claudia Burrello
- Department of Experimental Oncology, IEO, European Istitute of Oncology IRCCS, Milan, Italy
| | - Gabriella Pellegrino
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Maria Rita Giuffrè
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Giulia Lovati
- Department of Experimental Oncology, IEO, European Istitute of Oncology IRCCS, Milan, Italy
| | - Ilaria Magagna
- Department of Experimental Oncology, IEO, European Istitute of Oncology IRCCS, Milan, Italy
| | - Alice Bertocchi
- Department of Experimental Oncology, IEO, European Istitute of Oncology IRCCS, Milan, Italy
| | - Fulvia Milena Cribiù
- Pathology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Francesca Boggio
- Pathology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Fiorenzo Botti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.,General and Emergency Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Elena Trombetta
- Flow Cytometry Service, Clinical Chemistry and Microbiology Laboratory Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Laura Porretti
- Flow Cytometry Service, Clinical Chemistry and Microbiology Laboratory Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Antonio Di Sabatino
- First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Maurizio Vecchi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Maria Rescigno
- Department of Experimental Oncology, IEO, European Istitute of Oncology IRCCS, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Flavio Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.,Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Federica Facciotti
- Department of Experimental Oncology, IEO, European Istitute of Oncology IRCCS, Milan, Italy
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30
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Rizvi ZA, Puri N, Saxena RK. Evidence of CD1d pathway of lipid antigen presentation in mouse primary lung epithelial cells and its up-regulation upon Mycobacterium bovis BCG infection. PLoS One 2018; 13:e0210116. [PMID: 30596774 PMCID: PMC6312317 DOI: 10.1371/journal.pone.0210116] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 12/17/2018] [Indexed: 01/01/2023] Open
Abstract
Presentation of a prototype lipid antigen α-Galactosylceramide (αGC) was examined on primary epithelial cells derived from mouse lungs and on bronchoalveolar lavage (BAL) cells that essentially comprise alveolar macrophages. Presence of CD1d molecules coupled to αGC was demonstrated on both types of cells pre-treated with αGC, suggesting that both cell types are equipped to present lipid antigens. Internalization of Mycobacterium bovis Bacillus Calmette–Guérin (BCG: a prototype pathogen), a pre-requisite to the processing and presentation of protein as well as lipid antigens, was clearly demonstrated in primary lung epithelial (PLE) cells as well as BAL cells. Both PLE and BAL cells expressed CD1d molecule and a significant up-regulation of its expression occurred upon infection of these cells with BCG. Besides CD1d, the expression of other important molecules that participate in lipid antigen presentation pathway (i.e. microsomal triglyceride transfer protein (MTTP), scavenger receptor B1 (SR-B1) and Saposin) was also significantly upregulated in PLE and BAL cells upon BCG infection. In situ up-regulation of CD1d expression on lung epithelial cells was also demonstrated in the lungs of mice exposed intra-tracheally to BCG. Taken together these results suggest that lung epithelial cells may have the ability to present lipid antigens and this pathway seems to get significantly upregulated in response to BCG infection.
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Affiliation(s)
- Zaigham Abbas Rizvi
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, Delhi, India
| | - Niti Puri
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, Delhi, India
- * E-mail:
| | - Rajiv K. Saxena
- Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi, Delhi, India
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31
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Vorkas CK, Wipperman MF, Li K, Bean J, Bhattarai SK, Adamow M, Wong P, Aubé J, Juste MAJ, Bucci V, Fitzgerald DW, Glickman MS. Mucosal-associated invariant and γδ T cell subsets respond to initial Mycobacterium tuberculosis infection. JCI Insight 2018; 3:121899. [PMID: 30282828 PMCID: PMC6237486 DOI: 10.1172/jci.insight.121899] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 08/29/2018] [Indexed: 01/01/2023] Open
Abstract
Innate immune responses that control early Mtb infection are poorly understood, but understanding these responses may inform vaccination and immunotherapy strategies. Innate T cells that respond to conserved bacterial ligands such as mucosal-associated invariant T (MAIT) and γδ T cells are prime candidates to mediate these early innate responses but have not been examined in subjects who have been recently exposed to Mtb. We recruited a cohort living in the same household with an active tuberculosis (TB) case and examined the abundance and functional phenotypes of 3 innate T cell populations reactive to M. tuberculosis: γδ T, invariant NK T (iNKT), and MAIT cells. Both MAIT and γδ T cells from subjects with Mtb exposure display ex vivo phenotypes consistent with recent activation. However, both MAIT and γδ T cell subsets have distinct response profiles, with CD4+ MAIT and γδ T cells accumulating after infection. Examination of exposed but uninfected contacts demonstrates that resistance to initial infection is accompanied by robust MAIT cell CD25 expression and granzyme B production coupled with a depressed CD69 and IFNγ response. Finally, we demonstrate that MAIT cell abundance and function correlate with the abundance of specific gut microbes, suggesting that responses to initial infection may be modulated by the intestinal microbiome.
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Affiliation(s)
- Charles Kyriakos Vorkas
- Division of Infectious Diseases, Weill Cornell Medicine (WCM), New York, New York, USA
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA
| | - Matthew F. Wipperman
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA
- Clinical and Translational Science Center, WCM, New York, New York, USA
| | - Kelin Li
- Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - James Bean
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA
| | - Shakti K. Bhattarai
- Department of Bioengineering, University of Massachusetts, Dartmouth, North Dartmouth, Massachusetts, USA
| | - Matthew Adamow
- Immune Monitoring Core Facility, Ludwig Center for Cancer Immunotherapy, Sloan Kettering Institute, MSKCC, New York, New York, USA
| | - Phillip Wong
- Immune Monitoring Core Facility, Ludwig Center for Cancer Immunotherapy, Sloan Kettering Institute, MSKCC, New York, New York, USA
| | - Jeffrey Aubé
- Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | | | - Vanni Bucci
- Department of Bioengineering, University of Massachusetts, Dartmouth, North Dartmouth, Massachusetts, USA
| | - Daniel W. Fitzgerald
- Division of Infectious Diseases, Weill Cornell Medicine (WCM), New York, New York, USA
- GHESKIO Centers, Port-au-Prince, Haiti
- Center for Global Health, WCM, New York, New York, USA
| | - Michael S. Glickman
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA
- Division of Infectious Diseases, MSKCC, New York, New York, USA
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32
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Trottein F, Paget C. Natural Killer T Cells and Mucosal-Associated Invariant T Cells in Lung Infections. Front Immunol 2018; 9:1750. [PMID: 30116242 PMCID: PMC6082944 DOI: 10.3389/fimmu.2018.01750] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Accepted: 07/16/2018] [Indexed: 12/13/2022] Open
Abstract
The immune system has been traditionally divided into two arms called innate and adaptive immunity. Typically, innate immunity refers to rapid defense mechanisms that set in motion within minutes to hours following an insult. Conversely, the adaptive immune response emerges after several days and relies on the innate immune response for its initiation and subsequent outcome. However, the recent discovery of immune cells displaying merged properties indicates that this distinction is not mutually exclusive. These populations that span the innate-adaptive border of immunity comprise, among others, CD1d-restricted natural killer T cells and MR1-restricted mucosal-associated invariant T cells. These cells have the unique ability to swiftly activate in response to non-peptidic antigens through their T cell receptor and/or to activating cytokines in order to modulate many aspects of the immune response. Despite they recirculate all through the body via the bloodstream, these cells mainly establish residency at barrier sites including lungs. Here, we discuss the current knowledge into the biology of these cells during lung (viral and bacterial) infections including activation mechanisms and functions. We also discuss future strategies targeting these cell types to optimize immune responses against respiratory pathogens.
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Affiliation(s)
- François Trottein
- Univ. Lille, U1019 – UMR 8204 – CIIL – Centre d’Infection et d’Immunité de Lille, Lille, France
- Centre National de la Recherche Scientifique, UMR 8204, Lille, France
- Institut National de la Santé et de la Recherche Médicale U1019, Lille, France
- Centre Hospitalier Universitaire de Lille, Lille, France
- Institut Pasteur de Lille, Lille, France
| | - Christophe Paget
- Institut National de la Santé et de la Recherche Médicale U1100, Centre d’Etude des Pathologies Respiratoires (CEPR), Tours, France
- Université de Tours, Tours, France
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33
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Hapil FZ, Wingender G. The interaction between invariant Natural Killer T cells and the mucosal microbiota. Immunology 2018; 155:164-175. [PMID: 29893412 DOI: 10.1111/imm.12958] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 05/21/2018] [Indexed: 02/06/2023] Open
Abstract
The surface of mammalian bodies is colonized by a multitude of microbial organisms, which under normal conditions support the host and are considered beneficial commensals. This requires, however, that the composition of the commensal microbiota is tightly controlled and regulated. The host immune system plays an important role in the maintenance of this microbiota composition. Here we focus on the contribution of one particular immune cell type, invariant Natural Killer T (iNKT) cells, in this process. The iNKT cells are a unique subset of T cells characterized by two main features. First, they express an invariant T-cell receptor that recognizes glycolipid antigens presented by CD1d, a non-polymorphic major histocompatibility complex class I-like molecule. Second, iNKT cells develop as effector/memory cells and swiftly exert effector functions, like cytokine production and cytotoxicity, after activation. We outline the influence that the mucosal microbiota can have on iNKT cells, and how iNKT cells contribute to the maintenance of the microbiota composition.
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Affiliation(s)
| | - Gerhard Wingender
- Izmir Biomedicine and Genome Center, Balcova/Izmir, Turkey.,Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Balcova/Izmir, Turkey
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34
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Gras S, Van Rhijn I, Shahine A, Le Nours J. Molecular recognition of microbial lipid-based antigens by T cells. Cell Mol Life Sci 2018; 75:1623-1639. [PMID: 29340708 PMCID: PMC6328055 DOI: 10.1007/s00018-018-2749-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Revised: 12/17/2017] [Accepted: 01/08/2018] [Indexed: 02/06/2023]
Abstract
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.
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Affiliation(s)
- Stephanie Gras
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC, 3800, Australia
| | - Ildiko Van Rhijn
- Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital/Harvard Medical School, Boston, USA
- Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, University Utrecht, Utrecht, The Netherlands
| | - Adam Shahine
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC, 3800, Australia
| | - Jérôme Le Nours
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC, 3800, Australia.
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35
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Chancellor A, Gadola SD, Mansour S. The versatility of the CD1 lipid antigen presentation pathway. Immunology 2018; 154:196-203. [PMID: 29460282 DOI: 10.1111/imm.12912] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 02/12/2018] [Accepted: 02/14/2018] [Indexed: 12/19/2022] Open
Abstract
The family of non-classical major histocompatibility complex (MHC) class-I like CD1 molecules has an emerging role in human disease. Group 1 CD1 includes CD1a, CD1b and CD1c, which function to display lipids on the cell surface of antigen-presenting cells for direct recognition by T-cells. The recent advent of CD1 tetramers and the identification of novel lipid ligands has contributed towards the increasing number of CD1-restricted T-cell clones captured. These advances have helped to identify novel donor unrestricted and semi-invariant T-cell populations in humans and new mechanisms of T-cell recognition. However, although there is an opportunity to design broadly acting lipids and harness the therapeutic potential of conserved T-cells, knowledge of their role in health and disease is lacking. We briefly summarize the current evidence implicating group 1 CD1 molecules in infection, cancer and autoimmunity and show that although CD1 are not as diverse as MHC, recent discoveries highlight their versatility as they exhibit intricate mechanisms of antigen presentation.
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Affiliation(s)
- Andrew Chancellor
- Faculty of Medicine, Academic Unit of Clinical and Experimental Sciences, Southampton, UK
| | - Stephan D Gadola
- Faculty of Medicine, Academic Unit of Clinical and Experimental Sciences, Southampton, UK.,F.Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Salah Mansour
- Faculty of Medicine, Academic Unit of Clinical and Experimental Sciences, Southampton, UK
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36
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Krijgsman D, Hokland M, Kuppen PJK. The Role of Natural Killer T Cells in Cancer-A Phenotypical and Functional Approach. Front Immunol 2018. [PMID: 29535734 PMCID: PMC5835336 DOI: 10.3389/fimmu.2018.00367] [Citation(s) in RCA: 160] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Natural killer T (NKT) cells are a subset of CD1d-restricted T cells at the interface between the innate and adaptive immune system. NKT cells can be subdivided into functional subsets that respond rapidly to a wide variety of glycolipids and stress-related proteins using T- or natural killer (NK) cell-like effector mechanisms. Because of their major modulating effects on immune responses via secretion of cytokines, NKT cells are also considered important players in tumor immunosurveillance. During early tumor development, T helper (TH)1-like NKT cell subsets have the potential to rapidly stimulate tumor-specific T cells and effector NK cells that can eliminate tumor cells. In case of tumor progression, NKT cells may become overstimulated and anergic leading to deletion of a part of the NKT cell population in patients via activation-induced cell death. In addition, the remaining NKT cells become hyporesponsive, or switch to immunosuppressive TH2-/T regulatory-like NKT cell subsets, thereby facilitating tumor progression and immune escape. In this review, we discuss this important role of NKT cells in tumor development and we conclude that there should be three important focuses of future research in cancer patients in relation with NKT cells: (1) expansion of the NKT cell population, (2) prevention and breaking of NKT cell anergy, and (3) skewing of NKT cells toward TH1-like subsets with antitumor activity.
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Affiliation(s)
- Daniëlle Krijgsman
- Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.,Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | | | - Peter J K Kuppen
- Department of Surgery, Leiden University Medical Center, Leiden, Netherlands
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37
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Regulation of Humoral Immunity by CD1d-Restricted Natural Killer T Cells. Immunology 2018. [DOI: 10.1016/b978-0-12-809819-6.00005-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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38
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Goins CM, Schreidah CM, Dajnowicz S, Ronning DR. Structural basis for lipid binding and mechanism of the Mycobacterium tuberculosis Rv3802 phospholipase. J Biol Chem 2017; 293:1363-1372. [PMID: 29247008 DOI: 10.1074/jbc.ra117.000240] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 12/05/2017] [Indexed: 11/06/2022] Open
Abstract
The Mycobacterium tuberculosis rv3802c gene encodes an essential enzyme with thioesterase and phospholipase A activity. Overexpression of Rv3802 orthologs in Mycobacterium smegmatis and Corynebacterium glutamicum increases mycolate content and decreases glycerophospholipids. Although a role in modulating the lipid composition of the unique mycomembrane has been proposed, the true biological function of Rv3802 remains uncertain. In this study, we present the first M. tuberculosis Rv3802 X-ray crystal structure, solved to 1.7 Å resolution. On the basis of the binding of PEG molecules to Rv3802, we identified its lipid-binding site and the structural basis for phosphatidyl-based substrate binding and phospholipase A activity. We found that movement of the α8-helix affords lipid binding and is required for catalytic turnover through covalent tethering. We gained insights into the mechanism of acyl hydrolysis by observing differing arrangements of PEG and water molecules within the active site. This study provides structural insights into biological function and facilitates future structure-based drug design toward Rv3802.
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Affiliation(s)
- Christopher M Goins
- From the Department of Chemistry and Biochemistry, University of Toledo, Toledo, Ohio 43606-3390 and
| | - Celine M Schreidah
- From the Department of Chemistry and Biochemistry, University of Toledo, Toledo, Ohio 43606-3390 and
| | - Steven Dajnowicz
- From the Department of Chemistry and Biochemistry, University of Toledo, Toledo, Ohio 43606-3390 and.,the Biology and Soft Matter Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831
| | - Donald R Ronning
- From the Department of Chemistry and Biochemistry, University of Toledo, Toledo, Ohio 43606-3390 and
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39
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Activation of invariant natural killer T cells stimulated with microbial α-mannosyl glycolipids. Sci Rep 2017; 7:9703. [PMID: 28852174 PMCID: PMC5574887 DOI: 10.1038/s41598-017-10309-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 08/08/2017] [Indexed: 12/21/2022] Open
Abstract
Some synthetic and bacterial glycolipids presented by CD1d specifically activate invariant NKT (iNKT) cells bearing an invariant Vα14-Jα18 (mouse) or Vα24-Jα18 (human) TCR. The antigenic glycolipids identified to date consist of two hydrophobic chains and an α-glycoside in which the 2′-OH group is in the cis orientation toward the anomeric group, namely, either an α-galactoside or an α-glucoside. Several microbial α-mannosyl glycolipids, in which the 2′-OH group is in the trans orientation, were herein examined to establish whether they have potential to activate iNKT cells. We found that α-mannnosyl1-3 (6′-O-acyl α-mannosyl)-1-1 monoacylglycerol and cholesteryl 6′-O-acyl α-mannoside, found in Saccharopolyspora and Candida albicans, respectively, induced the activation of iNKT cells, dependent on CD1d. In contrast, α-mannosyldiacylglycerol found in Streptococcus suis or α-mannosylceramide demonstrated markedly less antigenicity for iNKT cells. The potentially antigenic α-mannosyl glycolipids contributed to the protection of mice against infection with S. pneumoniae in which iNKT cells have previously been found to participate. Furthermore, these glycolipids induced the production of proinflammatory cytokines by macrophages, thereby suggesting their recognition by specific pattern recognition receptors (PRRs). Collectively, these results suggest that these microbial α-mannosyl glycolipids are capable of being recognized by both the invariant TCR and PRRs and inducing immune responses.
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Keller CW, Freigang S, Lünemann JD. Reciprocal Crosstalk between Dendritic Cells and Natural Killer T Cells: Mechanisms and Therapeutic Potential. Front Immunol 2017; 8:570. [PMID: 28596767 PMCID: PMC5442181 DOI: 10.3389/fimmu.2017.00570] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 04/28/2017] [Indexed: 12/23/2022] Open
Abstract
Natural killer T cells carrying a highly conserved, semi-invariant T cell receptor (TCR) [invariant natural killer T (iNKT) cells] are a subset of unconventional T lymphocytes that recognize glycolipids presented by CD1d molecules. Although CD1d is expressed on a variety of hematopoietic and non-hematopoietic cells, dendritic cells (DCs) are key presenters of glycolipid antigen in vivo. When stimulated through their TCR, iNKT cells rapidly secrete copious amounts of cytokines and induce maturation of DCs, thereby facilitating coordinated stimulation of innate and adaptive immune responses. The bidirectional crosstalk between DCs and iNKT cells determines the functional outcome of iNKT cell-targeted responses and iNKT cell agonists are used and currently being evaluated as adjuvants to enhance the efficacy of antitumor immunotherapy. This review illustrates mechanistic underpinnings of reciprocal DCs and iNKT cell interactions and discusses how those can be harnessed for cancer therapy.
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Affiliation(s)
- Christian W Keller
- Institute of Experimental Immunology, Laboratory of Neuroinflammation, University of Zurich, Zurich, Switzerland
| | - Stefan Freigang
- Institute of Pathology, Laboratory of Immunopathology, University of Bern, Bern, Switzerland
| | - Jan D Lünemann
- Institute of Experimental Immunology, Laboratory of Neuroinflammation, University of Zurich, Zurich, Switzerland.,Department of Neurology, University Hospital Zurich, Zurich, Switzerland
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Kaczmarek R, Pasciak M, Szymczak-Kulus K, Czerwinski M. CD1: A Singed Cat of the Three Antigen Presentation Systems. Arch Immunol Ther Exp (Warsz) 2017; 65:201-214. [PMID: 28386696 PMCID: PMC5434122 DOI: 10.1007/s00005-017-0461-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 02/20/2017] [Indexed: 02/07/2023]
Abstract
Contrary to general view that the MHC Class I and II are the kapellmeisters of recognition and response to antigens, there is another big player in that part of immunity, represented by CD1 glycoproteins. In contrast to MHC Class I or II, which present peptides, CD1 molecules present lipids. Humans express five CD1 proteins (CD1a-e), four of which (CD1a-d) are trafficked to the cell surface, where they may display lipid antigens to T-cell receptors. This interaction may lead to both non-cognate and cognate T cell help to B cells, the latter eliciting anti-lipid antibody response. All CD1 proteins can bind a broad range of structurally different exogenous and endogenous lipids, but each shows a preference to one or more lipid classes. This unorthodox binding behavior is the result of elaborate architectures of CD1 binding clefts and distinct intracellular trafficking routes. Together, these features make CD1 system a versatile player in immune response, sitting at the crossroads of innate and adaptive immunity. While CD1 system may be involved in numerous infectious, inflammatory, and autoimmune diseases, its involvement may lead to opposite outcomes depending on different pathologies. Despite these ambiguities and complexity, CD1 system draws growing attention and continues to show glimmers of therapeutic potential. In this review, we summarize the current knowledge about CD1 proteins, their structures, lipid-binding profiles, and roles in immunity, and evaluate the role of CD1 proteins in eliciting humoral immune response.
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Affiliation(s)
- Radoslaw Kaczmarek
- Laboratory of Glycoconjugate Immunochemistry, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Mariola Pasciak
- Laboratory of Medical Microbiology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Katarzyna Szymczak-Kulus
- Laboratory of Glycoconjugate Immunochemistry, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Marcin Czerwinski
- Laboratory of Glycoconjugate Immunochemistry, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland. .,Faculty of Physiotherapy and Physical Education, Opole University of Technology, Opole, Poland.
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Ishikawa E, Mori D, Yamasaki S. Recognition of Mycobacterial Lipids by Immune Receptors. Trends Immunol 2017; 38:66-76. [DOI: 10.1016/j.it.2016.10.009] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 10/24/2016] [Accepted: 10/28/2016] [Indexed: 01/03/2023]
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Toyonaga K, Torigoe S, Motomura Y, Kamichi T, Hayashi JM, Morita YS, Noguchi N, Chuma Y, Kiyohara H, Matsuo K, Tanaka H, Nakagawa Y, Sakuma T, Ohmuraya M, Yamamoto T, Umemura M, Matsuzaki G, Yoshikai Y, Yano I, Miyamoto T, Yamasaki S. C-Type Lectin Receptor DCAR Recognizes Mycobacterial Phosphatidyl-Inositol Mannosides to Promote a Th1 Response during Infection. Immunity 2016; 45:1245-1257. [PMID: 27887882 DOI: 10.1016/j.immuni.2016.10.012] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2016] [Revised: 07/25/2016] [Accepted: 08/26/2016] [Indexed: 12/21/2022]
Abstract
Phosphatidyl-inositol mannosides (PIM) are glycolipids unique to mycobacteria and other related bacteria that stimulate host immune responses and are implicated in mycobacteria pathogenicity. Here, we found that the FcRγ-coupled C-type lectin receptor DCAR (dendritic cell immunoactivating receptor; gene symbol Clec4b1) is a direct receptor for PIM. Mycobacteria activated reporter cells expressing DCAR, and delipidation of mycobacteria abolished this activity. Acylated PIMs purified from mycobacteria were identified as ligands for DCAR. DCAR was predominantly expressed in small peritoneal macrophages and monocyte-derived inflammatory cells in lungs and spleen. These cells produced monocyte chemoattractant protein-1 (MCP-1) upon PIM treatment, and absence of DCAR or FcRγ abrogated MCP-1 production. Upon mycobacterial infection, Clec4b1-deficient mice showed reduced numbers of monocyte-derived inflammatory cells at the infection site, impaired IFNγ production by T cells, and an increased bacterial load. Thus, DCAR is a critical receptor for PIM that functions to promote T cell responses against mycobacteria.
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Affiliation(s)
- Kenji Toyonaga
- Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
| | - Shota Torigoe
- Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
| | - Yoshitomo Motomura
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Takane Kamichi
- Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan; Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences Kyushu University, Fukuoka 812-8582, Japan
| | - Jennifer M Hayashi
- Department of Microbiology, University of Massachusetts, Amherst, MA 01003, USA
| | - Yasu S Morita
- Department of Microbiology, University of Massachusetts, Amherst, MA 01003, USA
| | - Naoto Noguchi
- Division of Host Defense, Research Center for Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
| | | | | | | | - Hiroshi Tanaka
- Department of Applied Chemistry, Graduate School of Science and Technology, Tokyo Institute of Technology, Tokyo 152-8552, Japan
| | - Yoshiko Nakagawa
- Center for Animal Resources and Development, Kumamoto University, Kumamoto 860-0811, Japan
| | - Tetsushi Sakuma
- Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima 739-8526, Japan
| | - Masaki Ohmuraya
- Center for Animal Resources and Development, Kumamoto University, Kumamoto 860-0811, Japan
| | - Takashi Yamamoto
- Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima 739-8526, Japan
| | - Masayuki Umemura
- Molecular Microbiology Group, Department of Infectious Diseases, Tropical Biosphere Research Center, and Department of Host Defense, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0213, Japan
| | - Goro Matsuzaki
- Molecular Microbiology Group, Department of Infectious Diseases, Tropical Biosphere Research Center, and Department of Host Defense, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0213, Japan
| | - Yasunobu Yoshikai
- Division of Host Defense, Research Center for Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
| | - Ikuya Yano
- Japan BCG Laboratory, Kiyose 204-0022, Japan
| | - Tomofumi Miyamoto
- Department of Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Sho Yamasaki
- Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan; Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan.
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Modulation of Dendritic-Epithelial Cell Responses against Sphingomonas Paucimobilis by Dietary Fibers. Sci Rep 2016; 6:30277. [PMID: 27452116 PMCID: PMC4959002 DOI: 10.1038/srep30277] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 06/29/2016] [Indexed: 02/07/2023] Open
Abstract
Non-fermenting Gram-negative bacilli, such as Sphingomonas paucimobilis (S.paucimobilis), are among the most widespread causes of nosocomial infections. Up to now, no definitive guidelines exist for antimicrobial therapy for S. paucimobilis infections. As we have shown that some dietary fibers exhibit pronounced immune-regulatory properties, we hypothesized that specific immune active dietary fibers might modulate the responses against S. paucimobilis. We studied the immunomodulatory effects of dietary fibers against S. paucimobilis on cytokine release and maturation of human dendritic cells (DCs) in co-cultures of DCs and intestinal epithelial cells (IECs). S. paucimobilis infection resulted in increased release of pro-inflammatory cytokines and chemokines by DCs/IECs; these effects were strongly attenuated by specific dietary fibers. Chicory inulin, sugar beet pectin, and both starches had the strongest regulatory effects. IL-12 and TNF-α were drastically diminished upon exposure to chicory inulin and sugar beet pectin, or both starches. High-maize 260, was more effective in the reduction of chemokine release than the others fibers tested. In summary, chicory inulin, sugar beet pectin, High-maize 260, and Novelose 330 attenuate S. paucimobilis-induced cytokines. These results demonstrate that dietary fibers with a specific chemical composition can be used to manage immune responses against pathogens such as S. paucimobilis.
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Zajonc DM. The CD1 family: serving lipid antigens to T cells since the Mesozoic era. Immunogenetics 2016; 68:561-76. [PMID: 27368414 DOI: 10.1007/s00251-016-0931-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 06/22/2016] [Indexed: 12/20/2022]
Abstract
Class I-like CD1 molecules are in a family of antigen-presenting molecules that bind lipids and lipopeptides, rather than peptides for immune surveillance by T cells. Since CD1 lacks the high degree of polymorphism found in their major histocompatibility complex (MHC) class I molecules, different species express different numbers of CD1 isotypes, likely to be able to present structurally diverse classes of lipid antigens. In this review, we will present a historical overview of the structures of the different human CD1 isotypes and also discuss species-specific adaptations of the lipid-binding groove. We will discuss how single amino acid changes alter the shape and volume of the CD1 binding groove, how these minor changes can give rise to different numbers of binding pockets, and how these pockets affect the lipid repertoire that can be presented by any given CD1 protein. We will compare the structures of various lipid antigens and finally, we will discuss recognition of CD1-presented lipid antigens by antigen receptors on T cells (TCRs).
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Affiliation(s)
- Dirk M Zajonc
- Division of Cell Biology, La Jolla Institute for Allergy and Immunology (LJI), La Jolla, CA, 92037, USA. .,Department of Internal Medicine, Faculty of Medicine and Health Sciences, Ghent University, 9000, Ghent, Belgium.
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Invariant natural killer T cells: front line fighters in the war against pathogenic microbes. Immunogenetics 2016; 68:639-48. [PMID: 27368411 DOI: 10.1007/s00251-016-0933-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 04/21/2016] [Indexed: 12/22/2022]
Abstract
Invariant natural killer T (iNKT) cells constitute a unique subset of innate-like T cells that have been shown to have crucial roles in a variety of immune responses. iNKT cells are characterized by their expression of both NK cell markers and an invariant T cell receptor (TCR) α chain, which recognizes glycolipids presented by the MHC class I-like molecule CD1d. Despite having a limited antigen repertoire, the iNKT cell response can be very complex, and participate in both protective and harmful immune responses. The protective role of these cells against a variety of pathogens has been particularly well documented. Through the use of these pathogen models, our knowledge of the breadth of the iNKT cell response has been expanded. Specific iNKT cell antigens have been isolated from several different bacteria, from which iNKT cells are critical for protection in mouse models. These responses can be generated by direct, CD1d-mediated activation, or indirect, cytokine-mediated activation, or a combination of the two. This can lead to secretion of a variety of different Th1, Th2, or Th17 cytokines, which differentially impact the downstream immune response against these pathogens. This critical role is emphasized by the conservation of these cells between mice and humans, warranting further investigation into how iNKT cells participate in protective immune responses, with the ultimate goal of harnessing their potential for treatment.
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47
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Anderson CK, Brossay L. The role of MHC class Ib-restricted T cells during infection. Immunogenetics 2016; 68:677-91. [PMID: 27368413 DOI: 10.1007/s00251-016-0932-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 05/22/2016] [Indexed: 01/02/2023]
Abstract
Even though major histocompatibility complex (MHC) class Ia and many Ib molecules have similarities in structure, MHC class Ib molecules tend to have more specialized functions, which include the presentation of non-peptidic antigens to non-classical T cells. Likewise, non-classical T cells also have unique characteristics, including an innate-like phenotype in naïve animals and rapid effector functions. In this review, we discuss the role of MAIT and NKT cells during infection but also the contribution of less studied MHC class Ib-restricted T cells such as Qa-1-, Qa-2-, and M3-restricted T cells. We focus on describing the types of antigens presented to non-classical T cells, their response and cytokine profile following infection, as well as the overall impact of these T cells to the immune system.
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Affiliation(s)
- Courtney K Anderson
- Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Box G-B618, Providence, RI, 02912, USA
| | - Laurent Brossay
- Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Box G-B618, Providence, RI, 02912, USA.
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48
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Richardson MB, Torigoe S, Yamasaki S, Williams SJ. Mycobacterium tuberculosis β-gentiobiosyl diacylglycerides signal through the pattern recognition receptor Mincle: total synthesis and structure activity relationships. Chem Commun (Camb) 2016; 51:15027-30. [PMID: 26310657 DOI: 10.1039/c5cc04773k] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Mycobacterium tuberculosis H37Ra produces a range of immunogenic β-gentiobiosyl diacylglycerides. We report the total synthesis of several candidate structures and show that these compounds signal weakly through mouse, but not human, Mincle. Structure-activity relationships reveal a striking dependence upon acyl chain length for gentiobiosyl diacylglyceride signalling through Mincle. Significantly, a truncated β-glucosyl diglyceride was shown to provide potent signalling through both human and mouse Mincle and could activate murine bone marrow derived dendritic cells.
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Affiliation(s)
- Mark B Richardson
- School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Victoria 3010, Australia.
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49
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Synthetic glycolipid activators of natural killer T cells as immunotherapeutic agents. Clin Transl Immunology 2016; 5:e69. [PMID: 27195112 PMCID: PMC4855264 DOI: 10.1038/cti.2016.14] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Revised: 03/11/2016] [Accepted: 03/13/2016] [Indexed: 12/23/2022] Open
Abstract
Certain types of glycolipids have been found to have remarkable immunomodulatory properties as a result of their ability to activate specific T lymphocyte populations with an extremely wide range of immune effector properties. The most extensively studied glycolipid reactive T cells are known as invariant natural killer T (iNKT) cells. The antigen receptors of these cells specifically recognize certain glycolipids, most notably glycosphingolipids with α-anomeric monosaccharides, presented by the major histocompatibility complex class I-like molecule CD1d. Once activated, iNKT cells can secrete a very diverse array of pro- and anti-inflammatory cytokines to modulate innate and adaptive immune responses. Thus, glycolipid-mediated activation of iNKT cells has been explored for immunotherapy in a variety of disease states, including cancer and a range of infections. In this review, we discuss the design of synthetic glycolipid activators for iNKT cells, their impact on adaptive immune responses and their use to modulate iNKT cell responses to improve immunity against infections and cancer. Current challenges in translating results from preclinical animal studies to humans are also discussed.
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50
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Birkholz AM, Kronenberg M. Antigen specificity of invariant natural killer T-cells. Biomed J 2016; 38:470-83. [PMID: 27013447 PMCID: PMC6138764 DOI: 10.1016/j.bj.2016.01.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Accepted: 11/16/2015] [Indexed: 12/16/2022] Open
Abstract
Natural killer T-cells, with an invariant T-cell antigen receptor α-chain (iNKT cells), are unique and conserved subset of lymphocytes capable of altering the immune system through their rapid and potent cytokine responses. They are reactive to lipid antigens presented by the CD1d molecule, an antigen-presenting molecule that is not highly polymorphic. iNKT cell responses frequently involve mixtures of cytokines that work against each other, and therefore attempts are underway to develop synthetic antigens that elicit only strong interferon-gamma (IFNγ) or only strong interleukin-4 responses but not both. Strong IFNγ responses may correlate with tighter binding to CD1d and prolonged stimulation of iNKT cells, and this may be useful for vaccine adjuvants and for stimulating anti-tumor responses. iNKT cells are self-reactive although the structure of the endogenous antigen is controversial. By contrast, bacterial and fungal lipids that engage the T-cell receptor and activate IFNγ from iNKT cells have been identified from both pathogenic and commensal organisms and the responses are in some cases highly protective from pathogens in mice. It is possible that the expanding knowledge of iNKT cell antigens and iNKT cell activation will provide the basis for therapies for patients suffering from infectious and immune diseases and cancer.
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Affiliation(s)
- Alysia M Birkholz
- Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, USA; Division of Biological Sciences, University of California, San Diego, La Jolla, USA
| | - Mitchell Kronenberg
- Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, USA; Division of Biological Sciences, University of California, San Diego, La Jolla, USA.
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