DOCSLIB.ORG

Elevated Hepatic Cd1d Levels Coincide with Invariant NKT Cell Defects in Chronic Hepatitis B Virus Infection

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Elevated Hepatic Cd1d Levels Coincide with Invariant NKT Cell Defects in Chronic Hepatitis B Virus Infection Elevated Hepatic CD1d Levels Coincide with Invariant NKT Cell Defects in Chronic Hepatitis B Virus Infection This information is current as Xiaosheng Tan, Yajie Ding, Peng Zhu, Rui Dou, Zhihui of September 24, 2021. Liang, Daofeng Yang, Zhiyong Huang, Wei Wang, Xiongwen Wu and Xiufang Weng J Immunol published online 11 April 2018 http://www.jimmunol.org/content/early/2018/04/10/jimmun ol.1701801 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2018/04/11/jimmunol.170180 Material 1.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published April 11, 2018, doi:10.4049/jimmunol.1701801 The Journal of Immunology Elevated Hepatic CD1d Levels Coincide with Invariant NKT Cell Defects in Chronic Hepatitis B Virus Infection Xiaosheng Tan,* Yajie Ding,* Peng Zhu,† Rui Dou,* Zhihui Liang,* Daofeng Yang,‡ Zhiyong Huang,† Wei Wang,* Xiongwen Wu,* and Xiufang Weng* Activation of invariant NKT (iNKT) cells manifests antiviral immune responses in vivo. However, clinical trials have failed to show consistent hepatitis B virus (HBV) DNA reduction postadministration of iNKT cell–specific agonist a-galactosylceramide (a-GalCer). In this study, we aimed to investigate HBV infection–related iNKT cell defects and explore iNKT cell–based thera- peutic potential for chronic hepatitis B (CHB). Liver specimens from 30 HBV-infected hepatocellular carcinoma patients were collected for CD1d/hepatitis B surface Ag (HBsAg) staining and/or intrahepatic iNKT cell assay. Two hundred and six chronic HBV-infected patients (including 130 CHB patients) were enrolled in the study of circulating iNKT cell frequency and function. We found that liver and hepatoma tissue that positively stained for HBsAg had higher CD1d expression as compared with HBsAg Downloaded from negatively stained counterparts. The elevated CD1d expression in infected tissue is supposed to facilitate the iNKT cell–based antiviral effects locally. However, iNKT cell defects that related with disease progression suggested iNKT cells attenuated their effects during chronic HBV infection. The residual iNKT cells in CHB patients showed aberrant activation and hyporesponsive- ness to a-GalCer. Exogenous IL-2 fully rescued a-GalCer–induced expansion of iNKT cells from CHB patients, and synergistic effects of IL-2 and IL-15 helped to recover the CD1d-dependent IFN-g production. In conclusion, our results highlight the increased CD1d expression in HBV-infected liver and differential iNKT cell defects associated with disease progression during http://www.jimmunol.org/ chronic HBV infection. The reversibility of iNKT cell defects suggests protective immune responses could be partially recovered in CHB. The Journal of Immunology, 2018, 200: 000–000. hronic hepatitis B (CHB) caused by hepatitis B virus recover after viral clearance by the development of a vigorous (HBV) infection is associated with significant mortality immune response associated with acute inflammatory liver dis- C and morbidity (1). Approximately 15–40% of patients eases (3). However, 90% of neonates and 30–50% of children with CHB infection develop fibrotic reaction and cirrhosis, which under 5 y of age exposed to HBV become chronic carriers, are associated with over 50% of the total cases of hepatocellular resulting in over 240 million people being chronically infected by guest on September 24, 2021 carcinoma (HCC) worldwide (2). Most HBV-infected adults (4, 5). Besides aiding in transformation, HBV plays a crucial role in enhancing immune suppression (6). During chronic HBV in- fection, T cells lost effector function after exposure over decades *Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; to high levels of the virus (7). The failure of the immune system to †Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong Univer- eradicate the virus and to halt progression of HCC is closely linked ‡ sity of Science and Technology, Wuhan, Hubei 430030, China; and Department of with pathogenesis and the survival of patients with HBV infection Infectious Disease, Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, (8, 9). Therefore, reconstitution of an efficient anti-HBV immune re- China sponse is still a promising approach for treatment of hepatitis B (10). ORCIDs: 0000-0001-9920-1555 (X.T.); 0000-0003-3647-8201 (R.D.); 0000-0003- CD1d-restricted invariant NKT (iNKT) cells that recognize lipid 2625-2137 (X. Weng). Ags are characterized by expression of an invariant TCR a-chain Received for publication January 2, 2018. Accepted for publication March 15, 2018. (Va14Ja18 in mice; Va24Ja18 in human) paired with a limited This work was supported by the National Nature Science Foundation of China (Grant array of TCR b-chains (Vb8.2, Vb7, or Vb2 in mice; Vb11 in 31570913 to X. Weng and 31370885 to X. Wu) and the 973 Program from the human) (11). As one of the predominant lymphocyte populations Ministry of Science and Technology of China (2013 CB530505). in liver, iNKT cells are potent regulators of the local immune X.T. and X. Weng conceived and designed the experiments. X.T., Y.D., W.W., and R.D. performed the experiments. P.Z., D.Y., and Z.H. collected clinical samples. X.T., system (11). Upon activation, iNKT cells respond with robust Th1 P.Z., D.Y., Z.L., X. Wu, and X. Weng analyzed the data. X.T., X. Wu, and X. Weng and Th2 cytokine production, helping to modulate both innate and wrote the article. adaptive immune responses (12). Despite low frequency in hu- Address correspondence and reprint requests to Dr. Xiufang Weng and Dr. Xiongwen mans, iNKT cell activity is now recognized to play important roles Wu, Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, No. 13 Hangkong Road, Wuhan, in infectious disease (13). In humans with X-linked lymphopro- Hubei 430030, China. E-mail addresses: [email protected] (X. Weng) and liferative syndrome, a selective defect in iNKT cells is associated [email protected] (X. Wu) with lethal EBV infection and increased lymphoma (14, 15). Al- The online version of this article contains supplemental material. though studies on transgenic mouse models of HBV infection have Abbreviations used in this article: ALT, alanine aminotransferase; AST, aspartate suggested iNKT cell control of HBV replication (16), less is aminotransferase; CHB, chronic hepatitis B; ER, endoplasmic reticulum; FasL, Fas ligand; a-GalCer, a-galactosylceramide; HBeAb, hepatitis B e Ab; HBeAg, hepatitis known about the role of iNKT cells in chronic HBV infection in B e Ag; HBsAg, hepatitis B surface Ag; HBV, hepatitis B virus; HCC, hepatocellular humans. Current descriptions of frequency and functional status of carcinoma; HD, healthy donor; IC, inactive carrier; iNKT, invariant NKT; IT, im- iNKT cells are highly inconsistent in chronic HBV-infected mune tolerance; MNC, mononuclear cell. patients. Both increased circulating iNKT cell frequency with Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 elevated IFN-g production (17) and reduced circulating iNKT cell www.jimmunol.org/cgi/doi/10.4049/jimmunol.1701801 2 iNKT CELL DEFECTS IN CHRONIC HEPATITIS B frequency with preserved function (18) have been reported in Flow cytometry CHB patients. iNKT cells have also been implicated in liver injury PBS57/CD1d tetramer was kindly gifted by the National Institutes of Health and HCC through secreting IL-4 and IL-13 (19). Of note, char- Tetramer Core Facility. Cells were stained with PBS57/CD1d tetramer, acterization of iNKT cells and CD1d expression in HBV-infected corresponding Abs, and/or CFSE (Thermo Fisher). The IFN-g in-culture liver tissue is poorly elucidated. supernatant was determined by using Cytometric Bead Array Flex Sets Marine sponge–derived agent a-galactosylceramide (a-GalCer) (BD Biosciences). Data were collected using FACSVerse or LSR II cytometer (BD Biosciences) and analyzed by FlowJo software (Tree Star). is a specific agonist of iNKT cells and capable of expanding CFSE proliferation assay was analyzed by ModFit LT V3.2 (Verity Soft- iNKT cells in vivo and in vitro (20). Activation of iNKT cells by ware House). a-GalCer inhibits HBV replication and promotes the breakage of Immunofluorescence staining CD8+ T cell tolerance in HBV transgenic animals (21). Further- more, increased iNKT cell ratio is associated with enhanced an- Liver and hepatoma specimens were fixed in 4% paraformaldehyde, em- titumor effect against hepatitis B surface
Load more

Recommended publications
  • Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse
    Welcome to More Choice CD Marker Handbook For more information, please visit: Human bdbiosciences.com/eu/go/humancdmarkers Mouse bdbiosciences.com/eu/go/mousecdmarkers Human and Mouse CD Marker Handbook Human and Mouse CD Marker Key Markers - Human Key Markers - Mouse CD3 CD3 CD (cluster of differentiation) molecules are cell surface markers T Cell CD4 CD4 useful for the identification and characterization of leukocytes. The CD CD8 CD8 nomenclature was developed and is maintained through the HLDA (Human Leukocyte Differentiation Antigens) workshop started in 1982. CD45R/B220 CD19 CD19 The goal is to provide standardization of monoclonal antibodies to B Cell CD20 CD22 (B cell activation marker) human antigens across laboratories. To characterize or “workshop” the antibodies, multiple laboratories carry out blind analyses of antibodies. These results independently validate antibody specificity. CD11c CD11c Dendritic Cell CD123 CD123 While the CD nomenclature has been developed for use with human antigens, it is applied to corresponding mouse antigens as well as antigens from other species. However, the mouse and other species NK Cell CD56 CD335 (NKp46) antibodies are not tested by HLDA. Human CD markers were reviewed by the HLDA. New CD markers Stem Cell/ CD34 CD34 were established at the HLDA9 meeting held in Barcelona in 2010. For Precursor hematopoetic stem cell only hematopoetic stem cell only additional information and CD markers please visit www.hcdm.org. Macrophage/ CD14 CD11b/ Mac-1 Monocyte CD33 Ly-71 (F4/80) CD66b Granulocyte CD66b Gr-1/Ly6G Ly6C CD41 CD41 CD61 (Integrin b3) CD61 Platelet CD9 CD62 CD62P (activated platelets) CD235a CD235a Erythrocyte Ter-119 CD146 MECA-32 CD106 CD146 Endothelial Cell CD31 CD62E (activated endothelial cells) Epithelial Cell CD236 CD326 (EPCAM1) For Research Use Only.
    [Show full text]
  • Supplementary Table 1: Adhesion Genes Data Set
    Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like,
    [Show full text]
  • Preclinical Evaluation of Invariant Natural Killer T Cells Modified With
    International Journal of Molecular Sciences Article Preclinical Evaluation of Invariant Natural Killer T Cells Modified with CD38 or BCMA Chimeric Antigen Receptors for Multiple Myeloma Renée Poels 1,†, Esther Drent 1,†,‡, Roeland Lameris 2, Afroditi Katsarou 1, Maria Themeli 1, Hans J. van der Vliet 2,3, Tanja D. de Gruijl 2, Niels W. C. J. van de Donk 1 and Tuna Mutis 1,* 1 Cancer Center Amsterdam, Department of Haematology, Amsterdam UMC, VU Amsterdam, 1081 HV Amsterdam, The Netherlands; [email protected] (R.P.); [email protected] (E.D.); [email protected] (A.K.); [email protected] (M.T.); [email protected] (N.W.C.J.v.d.D.) 2 Cancer Center Amsterdam, Department of Medical Oncology, Amsterdam UMC, VU Amsterdam, 1081 HV Amsterdam, The Netherlands; [email protected] (R.L.); [email protected] (H.J.v.d.V.); [email protected] (T.D.d.G.) 3 Lava Therapeutics, 3584 CM Utrecht, The Netherlands * Correspondence: [email protected] † Equally contributed. ‡ Presently working at Gadeta, 3584 CM Utrecht, The Netherlands. Abstract: Due to the CD1d restricted recognition of altered glycolipids, Vα24-invariant natural killer T (iNKT) cells are excellent tools for cancer immunotherapy with a significantly reduced risk Citation: Poels, R.; Drent, E.; for graft-versus-host disease when applied as off-the shelf-therapeutics across Human Leukocyte Lameris, R.; Katsarou, A.; Themeli, Antigen (HLA) barriers. To maximally harness their therapeutic potential for multiple myeloma M.; van der Vliet, H.J.; de Gruijl, T.D.; (MM) treatment, we here armed iNKT cells with chimeric antigen receptors (CAR) directed against van de Donk, N.W.C.J.; Mutis, T.
    [Show full text]
  • Focused Transcription from the Human CR2/CD21 Core Promoter Is Regulated by Synergistic Activity of TATA and Initiator Elements in Mature B Cells
    Cellular & Molecular Immunology (2016) 13, 119–131 ß 2015 CSI and USTC. All rights reserved 1672-7681/15 $32.00 www.nature.com/cmi RESEARCH ARTICLE Focused transcription from the human CR2/CD21 core promoter is regulated by synergistic activity of TATA and Initiator elements in mature B cells Rhonda L Taylor1,2, Mark N Cruickshank3, Mahdad Karimi2, Han Leng Ng1, Elizabeth Quail2, Kenneth M Kaufman4,5, John B Harley4,5, Lawrence J Abraham1, Betty P Tsao6, Susan A Boackle7 and Daniela Ulgiati1 Complement receptor 2 (CR2/CD21) is predominantly expressed on the surface of mature B cells where it forms part of a coreceptor complex that functions, in part, to modulate B-cell receptor signal strength. CR2/CD21 expression is tightly regulated throughout B-cell development such that CR2/CD21 cannot be detected on pre-B or terminally differentiated plasma cells. CR2/CD21 expression is upregulated at B-cell maturation and can be induced by IL-4 and CD40 signaling pathways. We have previously characterized elements in the proximal promoter and first intron of CR2/CD21 that are involved in regulating basal and tissue-specific expression. We now extend these analyses to the CR2/CD21 core promoter. We show that in mature B cells, CR2/CD21 transcription proceeds from a focused TSS regulated by a non-consensus TATA box, an initiator element and a downstream promoter element. Furthermore, occupancy of the general transcriptional machinery in pre-B versus mature B-cell lines correlate with CR2/CD21 expression level and indicate that promoter accessibility must switch from inactive to active during the transitional B-cell window.
    [Show full text]
  • G( ) Anaerobes–Reactive CD4 T-Cells Trigger RANKL-Mediated
    G(؊) Anaerobes–Reactive CD4؉ T-Cells Trigger RANKL-Mediated Enhanced Alveolar Bone Loss in Diabetic NOD Mice Deeqa A. Mahamed,1,2 Annette Marleau,2 Mawadda Alnaeeli,1 Bhagirath Singh,2 Xiaoxia Zhang,1 Joseph M. Penninger,3 and Yen-Tung A. Teng1,2 Diabetic patients experience a higher risk for severe periodontitis; however, the underlying mechanism re- mains unclear. We investigated the contribution of anti- uman periodontal disease is a chronic inflamma- bacterial T-cell–mediated immunity to enhanced alveolar tory disease triggered by infection with specific bone loss during periodontal infection in nonobese subgingival microorganisms. Initially, inflam- diabetic (NOD) mice by oral inoculation with Actino- Hmation and bleeding of the gingival tissue (gin- bacillus actinomycetemcomitans,aG(؊) anaerobe givitis) prevails, followed by destruction of the supporting responsible for juvenile and severe periodontitis. The connective and bone tissues around the tooth (periodon- results show that 1) inoculation with A. actinomycetem- titis), eventually leading to tooth loss. Microbial species comitans in pre-diabetic NOD mice does not alter the such as Actinobacillus actinomycetemcomitans, Por- onset, incidence, and severity of diabetes; 2) after phorymonas gingivalis, Bacteriodes forsythus, and mixed A. actinomycetemcomitans inoculation, diabetic NOD spirochetes have been shown to be involved in the disease mice (blood glucose 200 mg/dl and with severe insuli- > pathogenesis, the development of which is further influ- tis) exhibit significantly higher alveolar bone loss com- pared with pre-diabetic and nondiabetic NOD mice; and enced by the host’s immune system, diet, oral hygiene, and ؉ Ϫ 3) A. actinomycetemcomitans–reactive CD4 T-cells in any genetic predisposition (1,2).
    [Show full text]
  • Cd1d Tetramer Α-Galcer Loaded (R-PE Labeled) Version 1.3
    PRODUCT SHEET CD1d Tetramer R-PE labeled α-GalCer Loaded: ▪ D001-2X ▪ E001-2X CD1d molecules are highly-conserved non-classical major histocompatibility complex (MHC) molecules that are characterized as non-polymorphic and possessing narrow, deep, hydrophobic ligand binding pockets. These binding pockets are capable of presenting glycolipids and phospholipids to Natural Killer T (NKT) cells. NKT cells represent a unique lymphocyte population that co-express NK cell markers and a semi-invariant T cell receptor (TCR), and are implicated in the regulation of immune responses associated with a broad range of diseases. The best-characterized CD1d ligand is α-galactosyl ceramide (α-GalCer), originally derived from marine sponge extract. Presentation of α-GalCer by CD1d molecules results in NKT cell recognition and rapid production of large amounts of IFN-γ and IL-4, bestowing α-GalCer with therapeutic efficacy. α-GalCer Loaded ProImmune’s fluorescent-labeled CD1d tetramers loaded with α-GalCer are used to identify Recombinant CD1d Natural Killer (NK) T cells. CD3+ NKT cells stained with CD1d Tetramer can be analyzed Tetramer: by flow cytometry and the frequency of antigen-specific NKT cells determined. Additional co-staining for intracellular cytokines (e.g. IFNγ / IL-2) or surface markers (e.g. CD69 / CD45RO) can provide additional functional data on the antigen-specific sub-set. For Research Use Only. Not for use in therapeutic or diagnostic procedures. Test Volume: 0.5 μl / test. Test Specification: One test contains sufficient reagent to stain approximately 1 × 106 cells. We recommend that the user titrate the reagent to determine the optimum amount to use in their specific application.
    [Show full text]
  • NKT Cells in Mucosal Immunity
    nature publishing group REVIEW See COMMENTARY page XX NKT cells in mucosal immunity S M i d d e n d o r p 1 a n d E E S N i e u w e n h u i s 1 The gastrointestinal tract allows the residence of an almost enumerable number of bacteria. To maintain homeostasis, the mucosal immune system must remain tolerant to the commensal microbiota and eradicate pathogenic bacteria. Aberrant interactions between the mucosal immune cells and the microbiota have been implicated in the pathogenesis of inflammatory disorders, such as inflammatory bowel disease (IBD). In this review, we discuss the role of natural killer T cells (NKT cells) in intestinal immunology. NKT cells are a subset of non-conventional T cells recognizing endogenous and / or exogenous glycolipid antigens when presented by the major histocompatibility complex (MHC) class I-like antigen-presenting molecules CD1d and MR1. Upon T-cell receptor (TCR) engagement, NKT cells can rapidly produce various cytokines that have important roles in mucosal immunity. Our understanding of NKT-cell-mediated pathways including the identification of specific antigens is expanding. This knowledge will facilitate the development of NKT cell- based interventions and immune therapies for human intestinal diseases. INTRODUCTION With reference to recent literature on the role of iNKT cells in The main function of the intestine is digestion and absorption mucosal immunology,2 – 4 this review will mainly focus on the of nutrients from food and recovery of water and electrolytes. role of other intestinal NKT cells (e.g., mucosal (m) NKT cells In addition, the intestine houses a large immune compartment, and NKT cells) in mucosal immunity and the interaction of as it is responsible for prevention and control of mucosal infec- NKT cells with other immune cells such as dendritic cells (DCs) tions, regulation of microbial colonization, and induction of oral and B lymphocytes.
    [Show full text]
  • Cd1d and Invariant NKT Cells at the Human Maternal–Fetal Interface
    CD1d and invariant NKT cells at the human maternal–fetal interface Jonathan E. Boyson*, Basya Rybalov*, Louise A. Koopman*, Mark Exley†, Steven P. Balk†, Frederick K. Racke‡, Frederick Schatz§, Rachel Masch§, S. Brian Wilson¶, and Jack L. Strominger*¶ʈ *Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138; †Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115; ‡Department of Pathology, Johns Hopkins University, Baltimore, MD 21287; §Department of Obstetrics and Gynecology, New York University Medical Center, New York, NY 10016; and ¶Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA 02115 Contributed by Jack L. Strominger, August 15, 2002 Invariant CD1d-restricted natural killer T (iNKT) cells comprise a selves play an active immunological role in regulating the small, but significant, immunoregulatory T cell subset. Here, the immune response to the fetal allograft because they express presence of these cells and their CD1d ligand at the human immunologically relevant molecules such as IL-10 (25, 26) and maternal–fetal interface was investigated. Immunohistochemical granulocyte͞macrophage colony-stimulating factor (GM-CSF) staining of human decidua revealed the expression of CD1d on receptor (27). both villous and extravillous trophoblasts, the fetal cells that Here, we demonstrate in humans the expression of CD1d on invade the maternal decidua. Decidual iNKT cells comprised 0.48% both villous and invasive extravillous fetal trophoblasts. In of the decidual CD3؉ T cell population, a frequency 10 times addition, human decidual iNKT cells, present at a frequency Ϸ10 greater than that seen in peripheral blood. Interestingly, decidual times that seen in peripheral blood, exhibited a marked Th1-like CD4؉ iNKT cells exhibited a striking Th1-like bias (IFN-␥ produc- cytokine bias as well as a striking polarization toward GM-CSF -tion), whereas peripheral blood CD4؉ iNKT clones exhibited a production.
    [Show full text]
  • Mrp1 Is Involved in Lipid Presentation and Inkt Cell Activation by Streptococcus Pneumoniae
    ARTICLE DOI: 10.1038/s41467-018-06646-8 OPEN Mrp1 is involved in lipid presentation and iNKT cell activation by Streptococcus pneumoniae Shilpi Chandra1, James Gray2, William B. Kiosses1, Archana Khurana1, Kaori Hitomi1, Catherine M. Crosby1, Ashu Chawla3, Zheng Fu 3, Meng Zhao1, Natacha Veerapen4, Stewart K. Richardson5, Steven A. Porcelli6, Gurdyal Besra 4, Amy R. Howell5, Sonia Sharma2,7, Bjoern Peters8,9 & Mitchell Kronenberg 1,10 Invariant natural killer T cells (iNKT cells) are activated by lipid antigens presented by CD1d, 1234567890():,; but the pathway leading to lipid antigen presentation remains incompletely characterized. Here we show a whole-genome siRNA screen to elucidate the CD1d presentation pathway. A majority of gene knockdowns that diminish antigen presentation reduced formation of glycolipid-CD1d complexes on the cell surface, including members of the HOPS and ESCRT complexes, genes affecting cytoskeletal rearrangement, and ABC family transporters. We validated the role in vivo for the multidrug resistance protein 1 (Mrp1) in CD1d antigen presentation. Mrp1 deficiency reduces surface clustering of CD1d, which decreased iNKT cell activation. Infected Mrp1 knockout mice show decreased iNKT cell responses to antigens from Streptococcus pneumoniae and were associated with increased mortality. Our results highlight the unique cellular events involved in lipid antigen presentation and show how modification of this pathway can lead to lethal infection. 1 Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. 2 The Functional Genomics Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. 3 Bioinformatics Core, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
    [Show full text]
  • Modulation of Cd1d-Restricted NKT Cell Responses by Using N-Acyl Variants of ␣-Galactosylceramides
    Modulation of CD1d-restricted NKT cell responses by using N-acyl variants of ␣-galactosylceramides Karl O. A. Yu*†, Jin S. Im*†, Alberto Molano*†, Yves Dutronc*‡, Petr A. Illarionov§, Claire Forestier*, Nagatoshi Fujiwara*¶, Isa Arias*, Sachiko Miyakeʈ, Takashi Yamamuraʈ, Young-Tae Chang**, Gurdyal S. Besra§, and Steven A. Porcelli*†† *Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461; §School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; ʈDepartment of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan; and **Department of Chemistry, New York University, 29 Washington Place, New York, NY 10003 Edited by Douglas T. Fearon, University of Cambridge, Cambridge, United Kingdom, and approved January 18, 2005 (received for review October 8, 2004) A form of ␣-galactosylceramide, KRN7000, activates CD1d-re- of their N-acyl substituents. Such modifications altered the stricted V␣14-invariant (V␣14i) natural killer (NK) T cells and outcome of V␣14i NKT cell activation and, in some cases, led to initiates multiple downstream immune reactions. We report that aTH2-biased and potentially antiinflammatory cytokine re- substituting the C26:0 N-acyl chain of KRN7000 with shorter, sponse. This change in the NKT cell response was likely the result unsaturated fatty acids modifies the outcome of V␣14i NKT cell of an alteration of downstream steps in the cascade of events activation. One analogue containing a diunsaturated C20 fatty acid triggered by V␣14i NKT cell activation, including the reduction (C20:2) potently induced a T helper type 2-biased cytokine re- of secondary activation of IFN-␥-producing NK cells.
    [Show full text]
  • CAR-Inkt Cells); Therapeutic Implications in Multiple Myeloma
    Papoutselis M, Spanoudakis E. Advances in Immunotherapy with Chimeric Antigen Receptor Invariant Natural Killer T cells (CAR-iNKT cells); Therapeutic Implications in Multiple Myeloma. Journal of J of Vaccinology. (2020);2(1):1-4 Vaccinology Mini review Article Open Access Advances in Immunotherapy with Chimeric Antigen Receptor Invariant Natural Killer T cells (CAR-iNKT cells); Therapeutic Implications in Multiple Myeloma Menelaos Papoutselis, Emmanouil Spanoudakis* Democritus University of Thrace, Medical School, Division of Hematology, Alexandroupolis, Greece Article Info Abstract Article Notes In Multiple Myeloma (MM), a highly CD1d expressing tumor, defects Received: May 8, 2020 in endogenous invariant Natural Killer T cells (iNKT cells) along with CD1d Accepted: June 27, 2020 downregulation through epigenetic silencing in advanced relapses, promotes *Correspondence: myeloma immune escape. Especially CD1d expression is totally lost on Emmanouil Spanoudakis, Assistant Professor of Hematology, plasma cells from extramedullary relapses and in myeloma cell lines, showing Democritus University of Thrace, Area of Dragana, that downregulation of CD1d on plasma cells happens when they become Alexandroupolis, 68100, Greece; independent from the bone marrow microenvironment. Myeloma cells Email: [email protected]. aberrantly overexpressed GM3, a glycolipid that promotes osteoclastogenesis ©2020 Spanoudakis E. This article is distributed under the terms and myeloma cell survival. A-galactosyl-ceramide, a glycolipid extracted from of the Creative Commons Attribution 4.0 International License. a marine sponge, can expand, and manipulate iNKT cell in-vivo but efforts to reverse iNKT cells defect and restore antimyeloma cytotoxicity with this agent, Keywords: failed. Advanced relapses of MM patients are difficult to treat and today CAR-T Multiple Myeloma cell based immunotherapeutic approaches are evolving with encouraging CD1d results.
    [Show full text]
  • Immune Regulation Via Cd1d-Dependent NKT Cells
    Going both ways: Immune regulation via CD1d-dependent NKT cells Dale I. Godfrey, Mitchell Kronenberg J Clin Invest. 2004;114(10):1379-1388. https://doi.org/10.1172/JCI23594. Review Series NKT cells are a unique T lymphocyte sublineage that has been implicated in the regulation of immune responses associated with a broad range of diseases, including autoimmunity, infectious diseases, and cancer. In stark contrast to both conventional T lymphocytes and other types of Tregs, NKT cells are reactive to the nonclassical class I antigen– presenting molecule CD1d, and they recognize glycolipid antigens rather than peptides. Moreover, they can either up- or downregulate immune responses by promoting the secretion of Th1, Th2, or immune regulatory cytokines. This review will explore the diverse influences of these cells in various disease models, their ability to suppress or enhance immunity, and the potential for manipulating these cells as a novel form of immunotherapy. Find the latest version: https://jci.me/23594/pdf Review series Going both ways: immune regulation via CD1d-dependent NKT cells Dale I. Godfrey1 and Mitchell Kronenberg2 1Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia. 2La Jolla Institute for Allergy and Immunology, San Diego, California, USA. NKT cells are a unique T lymphocyte sublineage that has been implicated in the regulation of immune responses associated with a broad range of diseases, including autoimmunity, infectious diseases, and cancer. In stark contrast to both conventional T lymphocytes and other types of Tregs, NKT cells are reactive to the nonclas- sical class I antigen–presenting molecule CD1d, and they recognize glycolipid antigens rather than peptides.
    [Show full text]