DOCSLIB.ORG

CD48 Is Critically Involved in Allergic Eosinophilic Airway Inflammation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
CD48 Is Critically Involved in Allergic Eosinophilic Airway Inflammation CD48 Is Critically Involved in Allergic Eosinophilic Airway Inflammation Ariel Munitz,1 Ido Bachelet,1 Fred D. Finkelman,2 Marc E. Rothenberg,3 and Francesca Levi-Schaffer1,4 1Department of Pharmacology, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; 2Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; 3Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio; and 4David R. Bloom Center for Pharmacology, Hebrew University of Jerusalem, Jerusalem, Israel Rationale: Despite ongoing research, the molecular mechanisms con- trolling asthma are still elusive. CD48 is a glycosylphosphatidylinositol- AT A GLANCE COMMENTARY anchored protein involved in lymphocyte adhesion, activation, and costimulation. Although CD48 is widely expressed on hematopoi- Scientific Knowledge on the Subject etic cells and commonly studied in the context of natural killer and CD48 is an activation molecule able to facilitate various cytotoxic T cell functions, its role in helper T cell type 2 settings cellular activities. Its role in asthma is unknown. has not been examined. Objectives: To evaluate the expression and function of CD48, CD2, and 2B4 in a murine model of allergic eosinophilic airway inflammation. What This Study Adds to the Field Methods: Allergic eosinophilic airway inflammation was induced by CD48 is upregulated in experimental asthma. Anti-CD48– ovalbumin (OVA)–alum sensitization and intranasal inoculation of based therapies may be useful for asthma and perhaps OVA or, alternatively, by repeated intranasal inoculation of Aspergil- various allergic diseases. lus fumigatus antigen in wild-type, STAT (signal transducer and acti- vator of transcription)-6–deficient, and IL-4/IL-13–deficient BALB/c mice. Gene profiling of whole lungs was performed, followed by Northern blot and flow cytometric analysis. Anti-CD48, -CD2, and -2B4 antibodies were administered before OVA challenge and cyto- the asthmatic lung leads to structural changes, which in turn exacer- kine expression and histology were assessed. bate the hyperresponsiveness observed in this disease (4). Measurements and Main Results: Microarray data analysis demon- Experimentation in the study of asthma has provided a ratio- strated upregulation of CD48 in the lungs of OVA-challenged mice. nale for the development of multiple therapeutic agents that Allergen-induced CD48 expression was independent of STAT-6, interfere with specific inflammatory pathways (5–8). However, IL-13, and IL-4. Neutralization of CD48 in allergen-challenged mice development of the disease phenotype is likely related to the abrogated bronchoalveolar lavage fluid and lung inflammation. interplay of a large number of pathways. Genome searches have Neutralization of CD2 inhibited the inflammatory response to a revealed that at least 19 genes contribute to asthma susceptibility lesser extent and neutralization of 2B4 had no effect. and microarray studies of asthmatic tissue revealed the involve- Conclusions: Our results suggest that CD48 is critically involved in ment of hundreds of genes (3). Moreover, microarray analysis allergic eosinophilic airway inflammation. As such, CD48 may pro- has demonstrated increased expression of 291 genes commonly vide a new potential target for the suppression of asthma. associated with murine disease pathogenesis rather than a par- ticular mode of disease induction (7). Therefore, a central issue Keywords: asthma; CD48; CD2; 2B4 still under investigation is the identification of fundamental molecules/pathways that govern the processes underlying in- Asthma is a chronic inflammatory disease of the airways charac- flammation in asthma. terized by airflow obstruction, bronchial hyperresponsiveness, CD48 is a glycosylphosphatidylinositol-anchored protein and airway inflammation (1–3). belonging to the CD2 subfamily (9). It is expressed mainly on Studies of airway inflammation in the lungs of individuals with hematopoietic cells and exists in both membrane-associated and asthma have revealed the accumulation of a large number of in- soluble forms (9, 10). It is a low-affinity ligand for CD2 and is flammatory cells, increased mucus production and submucosal mu- implicated as an important costimulatory molecule in lympho- cus gland hyperplasia/metaplasia, epithelial shedding, and smooth cyte activation (11, 12). Interestingly, whereas CD2-deficient muscle cell hypertrophy (3, 4). Notably, chronic inflammation of mice display normal T cell development and function, CD48- deficient mice exhibit significant defects in CD4ϩ T cell activation (13, 14), indicating a broad immunologic role for CD48. Indeed, CD48 has been described as facilitating cell adhesion (15, 16), (Received in original form May 24, 2006; accepted in final form February 7, 2007 ) innate responses to bacterial infection (17–19), and graft rejec- Supported in part by grants from the Aimwell Charitable Trust UK, by Israel Science tion (20–23). Foundation grant 213/05 (F.L.-S.), and by NIH grants R01 AI42242 (M.E.R.), R01 In addition, CD48 is a high-affinity ligand for 2B4 (24). CD48– AI45898 (M.E.R.), and P01 HL-076383-01 (M.E.R. and F.D.F.). 2B4 interactions can modulate T cell, B cell, and natural killer Correspondence and requests for reprints should be addressed to Francesca (NK) cell functions and cross-talk (25–27). Studies with 2B4 Levi-Schaffer, Ph.D., Department of Pharmacology, School of Pharmacy, Faculty gene–targeted mice demonstrated that 2B4–CD48 interactions of Medicine, Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem 91120, are essential for expansion and activation of murine NK cells Israel. E-mail: [email protected] (26). The absence of functional 2B4–CD48 interactions impairs This article has an online supplement, which is accessible from this issue’s table NK cell cytotoxic response and IFN-␥ release on tumor target of contents at www.atsjournals.org exposure (27). Furthermore, activated NK cells significantly Am J Respir Crit Care Med Vol 175. pp 911–918, 2007 ϩ ϩ Originally Published in Press as DOI: 10.1164/rccm.200605-695OC on February 8, 2007 increase the CD3-dependent proliferation of CD8 and CD4 Internet address: www.atsjournals.org T cells by a 2B4–CD48-dependent mechanism (25). 912 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 175 2007 The contribution of CD48 has not been explored in helper volume of 100 ␮l of Hanks’ balanced salt solution supplemented with T cell type 2 (Th2) settings. Thus, the applicability of CD48- 0.1% bovine serum albumin and 0.02% sodium azide for 30 minutes dependent stimulatory pathways that have been investigated in on ice. Thereafter, differential cell populations were electronically gated Th1 settings to allergy is not obvious. and assessed for expression of CD48, CD2, or 2B4. See the online supplement for additional detail on the method. In this study, we investigated the contribution of CD48 and its ligands to allergic eosinophilic airway inflammation. We re- Mediator Assessment port that CD48 is upregulated in two murine models of allergic Cytokines were measured with kits purchased from the following eosinophilic airway inflammation (7). Furthermore, experiments sources: IL-5 (eBioscience), IL-4 and IL-13 (BioLegend), and eotaxin-2 with anti-CD48, anti-CD2, and anti-2B4 neutralizing monoclonal and tumor necrosis factor (TNF)-␣ (R&D Systems). ELISA procedures antibodies (mAbs) demonstrate that CD48 is critically involved were performed according to the manufacturers’ instructions. Lower in allergic eosinophilic airway inflammation. detection limits for the various assays were as follows: 7.8, 2, 16, 32, and 16 pg/ml, respectively. METHODS Quantification of Lung Inflammation Reagents and Chemicals Histological studies were performed as follows: the right upper lobe of All chemicals used in this study were purchased from Sigma (Rehovot, saline or allergen-challenged lungs was fixed in 3.7% paraformaldehyde, Israel) and were of the best available grade. embedded in paraffin, deparaffinized, and stained with hematoxylin and eosin or with periodic acid–Schiff reagent. Antibodies See the online supplement for additional detail on the calculation Fluorescein isothiocyanate (FITC)-conjugated anti-CCR3 (CC chemo- method. kine receptor-3) was obtained from R&D Systems (Minneapolis, MN). Anti-CD3–allophycocyanin (APC), anti-VLA (very late activa- Statistical Analysis tion antigen)-4–phycoerythrin (PE) (clone DX5), anti-CD4–PE/cyanine Statistical significance was calculated by parametric analysis (analysis 5 (Cy5), anti-rat IgG–PE, anti-rat IgG–FITC, streptavidin–PE, and of variance, followed by the Tukey-Kramer post hoc test or Student streptavidin–Cy5 were all purchased from eBioscience (San Diego, t test). Values were considered significant at p Ͻ 0.05 (32). CA). Anti-B220–APC, anti-CD2, and anti-CD48–PE were obtained from BioLegend (San Diego, CA). Anti-2B4 mAb (a kind gift from RESULTS V. Kumar, University of Chicago, Chicago, IL) and anti-CD2 were conjugated to biotin according to a standard protocol (28). DNA Microarray Analysis Identifies CD48 as an Allergen- induced Gene in Allergic Eosinophilic Airway Inflammation Mice All experiments involving animals and primary animal cells were ap- Quantitative microarray analysis revealed that CD48, but not proved by the institutional animal experimentation ethics committee. CD2 or 2B4, mRNA expression was significantly increased in
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]
  • Human NK Cells with the 2B4 Receptor Inhibits Self-Killing of the Association of MHC Class I Proteins
    The Association of MHC Class I Proteins with the 2B4 Receptor Inhibits Self-Killing of Human NK Cells This information is current as Gili Betser-Cohen, Saar Mizrahi, Moran Elboim, Osnat of September 27, 2021. Alsheich-Bartok and Ofer Mandelboim J Immunol 2010; 184:2761-2768; Prepublished online 17 February 2010; doi: 10.4049/jimmunol.0901572 http://www.jimmunol.org/content/184/6/2761 Downloaded from References This article cites 39 articles, 14 of which you can access for free at: http://www.jimmunol.org/content/184/6/2761.full#ref-list-1 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 27, 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 © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology The Association of MHC Class I Proteins with the 2B4 Receptor Inhibits Self-Killing of Human NK Cells Gili Betser-Cohen, Saar Mizrahi, Moran Elboim, Osnat Alsheich-Bartok, and Ofer Mandelboim The killing activity of NK cells is carried out by several activating NK receptors, which includes NKp46, NKp44, NKp30, NKp80, NKG2D, and 2B4.
    [Show full text]
  • CD226 T Cells Expressing the Receptors TIGIT and Divergent Phenotypes of Human Regulatory
    The Journal of Immunology Divergent Phenotypes of Human Regulatory T Cells Expressing the Receptors TIGIT and CD226 Christopher A. Fuhrman,*,1 Wen-I Yeh,*,1 Howard R. Seay,* Priya Saikumar Lakshmi,* Gaurav Chopra,† Lin Zhang,* Daniel J. Perry,* Stephanie A. McClymont,† Mahesh Yadav,† Maria-Cecilia Lopez,‡ Henry V. Baker,‡ Ying Zhang,x Yizheng Li,{ Maryann Whitley,{ David von Schack,x Mark A. Atkinson,* Jeffrey A. Bluestone,‡ and Todd M. Brusko* Regulatory T cells (Tregs) play a central role in counteracting inflammation and autoimmunity. A more complete understanding of cellular heterogeneity and the potential for lineage plasticity in human Treg subsets may identify markers of disease pathogenesis and facilitate the development of optimized cellular therapeutics. To better elucidate human Treg subsets, we conducted direct transcriptional profiling of CD4+FOXP3+Helios+ thymic-derived Tregs and CD4+FOXP3+Helios2 T cells, followed by comparison with CD4+FOXP32Helios2 T conventional cells. These analyses revealed that the coinhibitory receptor T cell Ig and ITIM domain (TIGIT) was highly expressed on thymic-derived Tregs. TIGIT and the costimulatory factor CD226 bind the common ligand CD155. Thus, we analyzed the cellular distribution and suppressive activity of isolated subsets of CD4+CD25+CD127lo/2 T cells expressing CD226 and/or TIGIT. We observed TIGIT is highly expressed and upregulated on Tregs after activation and in vitro expansion, and is associated with lineage stability and suppressive capacity. Conversely, the CD226+TIGIT2 population was associated with reduced Treg purity and suppressive capacity after expansion, along with a marked increase in IL-10 and effector cytokine production. These studies provide additional markers to delineate functionally distinct Treg subsets that may help direct cellular therapies and provide important phenotypic markers for assessing the role of Tregs in health and disease.
    [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]
  • Cytokine-Enhanced Cytolytic Activity of Exosomes from NK Cells
    Cancer Gene Therapy https://doi.org/10.1038/s41417-021-00352-2 ARTICLE Cytokine-enhanced cytolytic activity of exosomes from NK Cells 1 1 2 3 2 3 Yutaka Enomoto ● Peng Li ● Lisa M. Jenkins ● Dimitrios Anastasakis ● Gaelyn C. Lyons ● Markus Hafner ● Warren J. Leonard 1 Received: 4 February 2021 / Revised: 9 May 2021 / Accepted: 18 May 2021 This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2021. This article is published with open access Abstract Natural killer (NK) cells play key roles in immune surveillance against tumors and viral infection. NK cells distinguish abnormal cells from healthy cells by cell–cell interaction with cell surface proteins and then attack target cells via multiple mechanisms. In addition, extracellular vesicles (EVs) derived from NK cells (NK-EVs), including exosomes, possess cytotoxic capacity against tumor cells, but their characteristics and regulation by cytokines remain unknown. Here, we report that EVs derived from human NK-92 cells stimulated with IL-15 + IL-21 show enhanced cytotoxic capacity against tumor cells. Major cytolytic granules, granzyme B and granzyme H, are enriched by IL-15 + IL-21 stimulation in NK-EVs; however, knockout experiments reveal those cytolytic granules are independent of enhanced cytotoxic capacity. To find out the key molecules, mass spectrometry analyses were 1234567890();,: 1234567890();,: performed with different cytokine conditions, no cytokine, IL-15, IL-21, or IL-15 + IL-21. We then found that CD226 (DNAM-1) on NK-EVs is enriched by IL-15 + IL-21 stimulation and that blocking antibodies against CD226 reduced the cytolytic activity of NK-EVs.
    [Show full text]
  • Binding Mode of the Side-By-Side Two-Igv Molecule CD226/DNAM-1 to Its Ligand CD155/Necl-5
    Binding mode of the side-by-side two-IgV molecule CD226/DNAM-1 to its ligand CD155/Necl-5 Han Wanga, Jianxun Qib, Shuijun Zhangb,1, Yan Lib, Shuguang Tanb,2, and George F. Gaoa,b,2 aResearch Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences (CAS), 100101 Beijing, China; and bCAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, 100101 Beijing, China Edited by K. Christopher Garcia, Stanford University School of Medicine, Stanford, CA, and approved December 3, 2018 (received for review September 11, 2018) Natural killer (NK) cells are important component of innate immu- CD226, also known as DNAM-1, belongs to the Ig superfamily nity and also contribute to activating and reshaping the adaptive and contains two extracellular Ig-like domains (CD226-D1 and immune responses. The functions of NK cells are modulated by CD226-D2), and is widely expressed in monocytes, platelets, multiple inhibitory and stimulatory receptors. Among these recep- T cells, and most of the resting NK cells (8, 13, 19, 20). The tors, the activating receptor CD226 (DNAM-1) mediates NK cell intracellular domain of CD226 does not contain a tyrosine-based activation via binding to its nectin-like (Necl) family ligand, CD155 activation motif, which is accepted as responsible for activating (Necl-5). Here, we present a unique side-by-side arrangement signal transduction of stimulatory molecules (13). Instead, it pattern of two tandem immunoglobulin V-set (IgV) domains transmits the downstream signaling by phosphorylation of in- deriving from the ectodomains of both human CD226 (hCD226- tracellular phosphorylation sites and subsequent association with ecto) and mouse CD226 (mCD226-ecto), which is substantially integrin lymphocyte function-associated antigen 1 (21).
    [Show full text]
  • CD Markers Are Routinely Used for the Immunophenotyping of Cells
    ptglab.com 1 CD MARKER ANTIBODIES www.ptglab.com Introduction The cluster of differentiation (abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules. So-called CD markers are routinely used for the immunophenotyping of cells. Despite this use, they are not limited to roles in the immune system and perform a variety of roles in cell differentiation, adhesion, migration, blood clotting, gamete fertilization, amino acid transport and apoptosis, among many others. As such, Proteintech’s mini catalog featuring its antibodies targeting CD markers is applicable to a wide range of research disciplines. PRODUCT FOCUS PECAM1 Platelet endothelial cell adhesion of blood vessels – making up a large portion molecule-1 (PECAM1), also known as cluster of its intracellular junctions. PECAM-1 is also CD Number of differentiation 31 (CD31), is a member of present on the surface of hematopoietic the immunoglobulin gene superfamily of cell cells and immune cells including platelets, CD31 adhesion molecules. It is highly expressed monocytes, neutrophils, natural killer cells, on the surface of the endothelium – the thin megakaryocytes and some types of T-cell. Catalog Number layer of endothelial cells lining the interior 11256-1-AP Type Rabbit Polyclonal Applications ELISA, FC, IF, IHC, IP, WB 16 Publications Immunohistochemical of paraffin-embedded Figure 1: Immunofluorescence staining human hepatocirrhosis using PECAM1, CD31 of PECAM1 (11256-1-AP), Alexa 488 goat antibody (11265-1-AP) at a dilution of 1:50 anti-rabbit (green), and smooth muscle KD/KO Validated (40x objective). alpha-actin (red), courtesy of Nicola Smart. PECAM1: Customer Testimonial Nicola Smart, a cardiovascular researcher “As you can see [the immunostaining] is and a group leader at the University of extremely clean and specific [and] displays Oxford, has said of the PECAM1 antibody strong intercellular junction expression, (11265-1-AP) that it “worked beautifully as expected for a cell adhesion molecule.” on every occasion I’ve tried it.” Proteintech thanks Dr.
    [Show full text]
  • Cytokine Regulation in Human CD4 T Cells by the Aryl Hydrocarbon
    www.nature.com/scientificreports OPEN Cytokine Regulation in Human CD4 T Cells by the Aryl Hydrocarbon Receptor and Gq-Coupled Received: 17 November 2017 Accepted: 9 July 2018 Receptors Published: xx xx xxxx Jeremy P. McAleer1, Jun Fan2, Bryanna Roar1, Donald A. Primerano2 & James Denvir2 Th17 cells contribute to host defense on mucosal surfaces but also provoke autoimmune diseases when directed against self-antigens. Identifying therapeutic targets that regulate Th17 cell diferentiation and/or cytokine production has considerable value. Here, we study the aryl hydrocarbon receptor (AhR)- dependent transcriptome in human CD4 T cells treated with Th17-inducing cytokines. We show that the AhR reciprocally regulates IL-17 and IL-22 production in human CD4 T cells. Global gene expression analysis revealed that AhR ligation decreased IL21 expression, correlating with delayed upregulation of RORC during culture with Th17-inducing cytokines. Several of the AhR-dependent genes have known roles in cellular assembly, organization, development, growth and proliferation. We further show that expression of GPR15, GPR55 and GPR68 positively correlates with IL-22 production in the presence of the AhR agonist FICZ. Activation of GPR68 with the lorazepam derivative ogerin resulted in suppression of IL-22 and IL-10 secretion by T cells, with no efect on IL-17. Under neutral Th0 conditions, ogerin and the Gq/11 receptor inhibitor YM254890 blunted IL-22 induction by FICZ. These data reveal the AhR- dependent transcriptome in human CD4 T cells and suggest the mechanism through which the AhR regulates T cell function may be partially dependent on Gq-coupled receptors including GPR68.
    [Show full text]
  • The Immunological Synapse and CD28-CD80 Interactions Shannon K
    © 2001 Nature Publishing Group http://immunol.nature.com ARTICLES The immunological synapse and CD28-CD80 interactions Shannon K. Bromley1,Andrea Iaboni2, Simon J. Davis2,Adrian Whitty3, Jonathan M. Green4, Andrey S. Shaw1,ArthurWeiss5 and Michael L. Dustin5,6 Published online: 19 November 2001, DOI: 10.1038/ni737 According to the two-signal model of T cell activation, costimulatory molecules augment T cell receptor (TCR) signaling, whereas adhesion molecules enhance TCR–MHC-peptide recognition.The structure and binding properties of CD28 imply that it may perform both functions, blurring the distinction between adhesion and costimulatory molecules. Our results show that CD28 on naïve T cells does not support adhesion and has little or no capacity for directly enhancing TCR–MHC- peptide interactions. Instead of being dependent on costimulatory signaling, we propose that a key function of the immunological synapse is to generate a cellular microenvironment that favors the interactions of potent secondary signaling molecules, such as CD28. The T cell receptor (TCR) interaction with complexes of peptide and as CD2 and CD48, which suggests that CD28 might have a dual role as major histocompatibility complex (pMHC) is central to the T cell an adhesion and a signaling molecule4. Coengagement of CD28 with response. However, efficient T cell activation also requires the partici- the TCR has a number of effects on T cell activation; these include pation of additional cell-surface receptors that engage nonpolymorphic increasing sensitivity to TCR stimulation and increasing the survival of ligands on antigen-presenting cells (APCs). Some of these molecules T cells after stimulation5. CD80-transfected APCs have been used to are involved in the “physical embrace” between T cells and APCs and assess the temporal relationship of TCR and CD28 signaling, as initiat- are characterized as adhesion molecules.
    [Show full text]
  • Proliferation by 2B4/CD48 Interactions T Cell
    Cutting Edge: Regulation of CD8+ T Cell Proliferation by 2B4/CD48 Interactions Taku Kambayashi, Erika Assarsson, Benedict J. Chambers and Hans-Gustaf Ljunggren This information is current as of September 29, 2021. J Immunol 2001; 167:6706-6710; ; doi: 10.4049/jimmunol.167.12.6706 http://www.jimmunol.org/content/167/12/6706 Downloaded from References This article cites 23 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/167/12/6706.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 *average by guest on September 29, 2021 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 © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. ● Cutting Edge: Regulation of CD8؉ T Cell Proliferation by 2B4/CD48 Interactions1 Taku Kambayashi,2* Erika Assarsson,2* Benedict J. Chambers,* and Hans-Gustaf Ljunggren3*† To date, the only known 2B4-binding molecule is CD48. Bind- The biological function of 2B4, a CD48-binding molecule ex- ing studies have shown that CD48 has a 5–10 times stronger af- pressed on T cells with an activation/memory phenotype, is not finity for 2B4 than for CD2 (7, 8).
    [Show full text]
  • CD226 Axis Fact Sheet
    Exploring the potential of next generation immuno-oncology therapies for cancer Until recently, standard treatments for What are checkpoint cancer included: inhibitors? T cells are an important part of our immune system and produce proteins called checkpoints which help keep the immune system in surgery radiotherapy “check” by not acting too aggressively. However, the checkpoints can also prevent T cells from recognising and killing cancer cells. When these checkpoints are blocked with chemotherapy targeted therapy certain medications, called checkpoint inhibitors, T cells function better and can attack cancer cells. The leading type However, immuno-oncology (IO) has emerged of checkpoint inhibitors include as a novel treatment approach by harnessing those targeting and the body’s own immune system to fight cancer. blocking PD-1/PD-L1. While IO therapies have transformed cancer Tumour cell care, unfortunately, not all patients benefit. One T cell of the most widely used types of IO therapies, checkpoint inhibitors, have only demonstrated response rates of 15 to 30% across most solid tumours.i Checkpoint inhibitor Targeting the CD226 axis CD226 is a molecule expressed on the surface of T cells and natural killer (NK) cells, which binds to CD155 and CD112 on tumour cells, stimulating an immune response. However, the immune checkpoints TIGIT, CD96 and PVRIG may prevent CD226 from interacting with CD155 and CD112, which may result in a reduced immune response and the development or progression of cancer. Blocking the CD96, PVRIG and TIGIT checkpoints may enable T and NK cells to better target tumour cells. We are uniquely positioned to explore innovative combinations with our CD226 axis checkpoint inhibitors – key targets for next-generation immuno-oncology therapies We are exploring potential therapeutic approaches to better understand how and when these assets may be used to improve outcomes for patients with cancer.
    [Show full text]
  • CD29 Identifies IFN-Γ–Producing Human CD8+ T Cells with an Increased Cytotoxic Potential
    + CD29 identifies IFN-γ–producing human CD8 T cells with an increased cytotoxic potential Benoît P. Nicoleta,b, Aurélie Guislaina,b, Floris P. J. van Alphenc, Raquel Gomez-Eerlandd, Ton N. M. Schumacherd, Maartje van den Biggelaarc,e, and Monika C. Wolkersa,b,1 aDepartment of Hematopoiesis, Sanquin Research, 1066 CX Amsterdam, The Netherlands; bLandsteiner Laboratory, Oncode Institute, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; cDepartment of Research Facilities, Sanquin Research, 1066 CX Amsterdam, The Netherlands; dDivision of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; and eDepartment of Molecular and Cellular Haemostasis, Sanquin Research, 1066 CX Amsterdam, The Netherlands Edited by Anjana Rao, La Jolla Institute for Allergy and Immunology, La Jolla, CA, and approved February 12, 2020 (received for review August 12, 2019) Cytotoxic CD8+ T cells can effectively kill target cells by producing therefore developed a protocol that allowed for efficient iso- cytokines, chemokines, and granzymes. Expression of these effector lation of RNA and protein from fluorescence-activated cell molecules is however highly divergent, and tools that identify and sorting (FACS)-sorted fixed T cells after intracellular cytokine + preselect CD8 T cells with a cytotoxic expression profile are lacking. staining. With this top-down approach, we performed an un- + Human CD8 T cells can be divided into IFN-γ– and IL-2–producing biased RNA-sequencing (RNA-seq) and mass spectrometry cells. Unbiased transcriptomics and proteomics analysis on cytokine- γ– – + + (MS) analyses on IFN- and IL-2 producing primary human producing fixed CD8 T cells revealed that IL-2 cells produce helper + + + CD8 Tcells.
    [Show full text]