DOCSLIB.ORG

Regulatory T Cells in Ovarian Cancer Are Characterized by a Highly Activated Phenotype Distinct from That in Melanoma Aras Toker1, Linh T

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Regulatory T Cells in Ovarian Cancer Are Characterized by a Highly Activated Phenotype Distinct from That in Melanoma Aras Toker1, Linh T Published OnlineFirst July 31, 2018; DOI: 10.1158/1078-0432.CCR-18-0554 Biology of Human Tumors Clinical Cancer Research Regulatory T Cells in Ovarian Cancer Are Characterized by a Highly Activated Phenotype Distinct from that in Melanoma Aras Toker1, Linh T. Nguyen1, Simone C. Stone1, S.Y. Cindy Yang2, Sarah Rachel Katz3, Patricia A. Shaw4, Blaise A. Clarke4, Danny Ghazarian4, Ayman Al-Habeeb4, Alexandra Easson5, Wey L. Leong5, David R. McCready5, Michael Reedijk1,2,5, Cynthia J. Guidos6,7, Trevor J. Pugh2,8, Marcus Q. Bernardini3, and Pamela S. Ohashi1,2,6 Abstract Purpose: Regulatory T (Treg) cells expressing the transcrip- number of receptors associated with TCR engagement, includ- tion factor FOXP3 are essential for the maintenance of immu- ing PD-1, 4-1BB, and ICOS. Higher PD-1 and 4-1BB expression nologic self-tolerance but play a detrimental role in most was associated with increased responsiveness to further TCR cancers due to their ability to suppress antitumor immunity. stimulation and increased suppressive capacity, respectively. The phenotype of human circulating Treg cells has been Transcriptomic and mass cytometry analyses revealed the extensively studied, but less is known about tumor-infiltrating presence of Treg cell subpopulations and further supported Treg cells. We studied the phenotype and function of tumor- a highly activated state specifically in ovarian tumors. In infiltrating Treg cells in ovarian cancer and melanoma to comparison, Treg cells infiltrating melanomas displayed identify potential Treg cell–associated molecules that can be lower FOXP3, PD-1, 4-1BB, and ICOS expression and were targeted by tumor immunotherapies. less potent suppressors of CD8 T-cell proliferation. Experimental Design: The phenotype of intratumoral Conclusions: The highly activated phenotype of ovarian and circulating Treg cells was analyzed by multicolor tumor-infiltrating Treg cells may be a key component of an flow cytometry, mass cytometry, RNA-seq, and functional immunosuppressive tumor microenvironment. Receptors assays. that are expressed by tumor-infiltrating Treg cells could be Results: Treg cells isolated from ovarian tumors displayed exploited for the design of novel combination tumor immu- a distinct cell surface phenotype with increased expression of a notherapies. Clin Cancer Res; 1–12. Ó2018 AACR. Introduction to uncover the mechanism of action and to identify biomarkers associated with response or resistance in order to establish The unprecedented success of immune checkpoint inhibitors guidelines for patient selection and provide a rationale for the has fueled efforts to further explore, expand, and develop novel development of combination immunotherapies (3, 4). cancer immunotherapy approaches. However, the mechanism Mechanisms of immune suppression within the tumor micro- of action of checkpoint inhibitors is not clear and response environment have been of particular focus, including the upre- rates are highly variable, and typically lower than 50%, across gulation of inhibitory molecules and the recruitment of sup- different cancers (1, 2). Therefore, research has been intensified pressive cell populations such as myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), and reg- ulatory T (Treg) cells (5–7). 1The Campbell Family Institute for Breast Cancer Research, Princess Margaret Treg cells are essential for the maintenance of immunologic Cancer Centre, University Health Network, Toronto, Ontario, Canada. self-tolerance and the prevention of autoimmunity (8). The 2Department of Medical Biophysics, University of Toronto, Toronto, Ontario, 3 transcription factor FoxP3 is a master regulator of Treg cell Canada. Division of Gynecologic Oncology, University Health Network, fi Toronto, Ontario, Canada. 4Department of Laboratory Medicine and Pathobi- function, and its de ciency leads to devastating autoimmune ology, University Health Network, University of Toronto, Toronto, Ontario, pathology in mice (8) and humans (9). In mice expression of Canada. 5Department of Surgical Oncology, University Health Network, Toronto, FoxP3 protein is strictly restricted to bona fide suppressive Treg Ontario, Canada. 6Department of Immunology, University of Toronto, Toronto, cells, whereas in humans, effector T cells without suppressive Ontario, Canada. 7Program in Developmental and Stem Cell Biology, Hospital for 8 function can also transiently express low levels of FoxP3 upon Sick Children Research Institute, Toronto, Ontario, Canada. Princess Margaret activation (10). Among many mechanisms Treg cells deploy to Genomics Centre, University Health Network, Toronto, Ontario, Canada. exhibit their immunosuppressive function are direct lysis of Note: Supplementary data for this article are available at Clinical Cancer immune effector cells, depletion of growth factors and metabo- Research Online (http://clincancerres.aacrjournals.org/). lites, inhibition of antigen-presenting cell function, and secretion Corresponding Author: Pamela S. Ohashi, Princess Margaret Cancer Centre, 610 of regulatory cytokines (9). University Avenue, Suite 8-407, Toronto, Ontario, Canada M5G 2C9. Phone: 416- The majority of circulating Treg cells belong to a distinct 946-4501, ext. 3689; Fax: 416-204-2276; E-mail: [email protected] þ and phenotypically stable lineage of CD4 T cells in mice and doi: 10.1158/1078-0432.CCR-18-0554 humans, as the expression of the master transcription factor Ó2018 American Association for Cancer Research. FoxP3 is initiated and epigenetically imprinted during thymic www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst July 31, 2018; DOI: 10.1158/1078-0432.CCR-18-0554 Toker et al. Translational Relevance Materials and Methods Study participants Rates of response to immunotherapy in ovarian cancer are All human tissue and blood were obtained through protocols low despite pronounced immune infiltration. Regulatory approved by the Institutional Review Board in concordance with T (Treg) cells infiltrate many human tumors and are in most the Declaration of Helsinki. Written informed consent was cases associated with poor prognosis. In this study, we obtained from all donors who provided the samples. found that tumor-infiltrating Treg cells express a distinct array of targetable immunoreceptors, and are highly acti- Tumor specimens vated and potently suppressive. Melanoma-infiltrating Treg Tumor specimens were obtained from the UHN Biospecimen cells share many features of this Treg cell phenotype, but Program, through surgical resection from patients diagnosed possess distinct differences that could require reconsidera- with epithelial ovarian cancer (mostly high-grade serous) or tion and adjustment of immunotherapeutic approaches melanoma. Patient characteristics are summarized in Supplemen- according to cancer type. A highly suppressive tumor micro- tary Table S1. Fresh tumor specimens were enzymatically digested environment could also explain the low response rate in (RPMI1640 containing 2 mmol/L L-glutamine, 1 mg/mL colla- ovarian cancer and suggests that combination therapies that genase, 10 mg/mL Pulmozyme, 100 U/mL penicillin, 100 mg/mL boost antitumor immunity and diminish immunosuppres- streptomycin, 10 mg/mL gentamicin sulfate, and 1.25 mg/mL sion could be more promising. The Treg cell expression Amphotericin B) using the GentleMACS system (Miltenyi Biotec). pattern of inhibitory receptors could become an important Tumor digests were cryopreserved in human serum containing factor to consider in treatment decisions to avoid unwanted 10% DMSO prior to analysis. A total of 2.2 Â 107 (Æ1.7 Â 107) increases in Treg cell–mediated immunosuppression by and 1.1 Â 107 (Æ1.3 Â 107) cells were processed and analyzed per cytotoxic T-cell–targeted immunotherapy regimens. ovarian tumor and melanoma specimen, respectively. Cell via- bility for the ovarian and melanoma specimens was 61.7% (Æ22.4%) and 43.0% (Æ29.1%), respectively (Supplementary Table S1). development (11, 12). However, a subset of Treg cells also retains plasticity and can revert to a phenotype with diminished Flow cytometry and cell sorting suppressive function and produce IFNg or IL17 under inflam- Cells were stained with anti-CD3 (clone OKT3), anti-CD4 þ matory conditions (13, 14). FOXP3 -suppressive Treg cells can (RPA-T4), anti-CD8 (RPA-T8), anti–PD-1 (eBioJ105), anti–4-1BB À also be induced in vivo from FOXP3 conventional T cells by (4B4-1), anti–TIM-3 (344823), anti-OX40 (Ber-ACT35), anti- stimulation in the presence of TGFb (15). Hence, the pool of TIGIT (MBSA43), anti–DNAM-1 (DX11), anti-CD27 (O323), circulating Treg cells consists of thymus-derived and peripherally anti-CD28 (CD28.2), anti-CD25 (M-A251), anti-ICOS (C398.4A), induced subsets, and the relative contribution of each subset to anti-CD45RA (HI100), and anti-CD127 (A019D5). Cells were stable and plastic Treg cell subpopulations has not been exten- fixed and permeabilized with the Foxp3 transcription factor sively studied. staining buffer set followed by intracellular staining with anti- Treg cells accumulate at the tumor site in many cancers FOXP3 (236A/E7) and anti–CTLA-4 (BNI3). Samples were including head and neck, colorectal, liver, lung, breast, ovarian, acquired on a BD LSR Fortessa SORP flow cytometer and data skin, and pancreas (5). A high prevalence of Treg cells within were analyzed using the FlowJo software. tumor-infiltrating lymphocytes (TIL) is associated
Load more

Recommended publications
  • Antibody-Dependent Cellular Cytotoxicity Riiia and Mediate Γ
    Effector Memory αβ T Lymphocytes Can Express Fc γRIIIa and Mediate Antibody-Dependent Cellular Cytotoxicity This information is current as Béatrice Clémenceau, Régine Vivien, Mathilde Berthomé, of September 27, 2021. Nelly Robillard, Richard Garand, Géraldine Gallot, Solène Vollant and Henri Vié J Immunol 2008; 180:5327-5334; ; doi: 10.4049/jimmunol.180.8.5327 http://www.jimmunol.org/content/180/8/5327 Downloaded from References This article cites 43 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/180/8/5327.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 © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Effector Memory ␣␤ T Lymphocytes Can Express Fc␥RIIIa and Mediate Antibody-Dependent Cellular Cytotoxicity1 Be´atrice Cle´menceau,*† Re´gine Vivien,*† Mathilde Berthome´,*† Nelly Robillard,‡ Richard Garand,‡ Ge´raldine Gallot,*† Sole`ne Vollant,*† and Henri Vie´2*† Human memory T cells are comprised of distinct populations with different homing potential and effector functions: central memory T cells that mount recall responses to Ags in secondary lymphoid organs, and effector memory T cells that confer immediate protection in peripheral tissues.
    [Show full text]
  • A Novel CD4+ CTL Subtype Characterized by Chemotaxis and Inflammation Is Involved in the Pathogenesis of Graves’ Orbitopa
    Cellular & Molecular Immunology www.nature.com/cmi ARTICLE OPEN A novel CD4+ CTL subtype characterized by chemotaxis and inflammation is involved in the pathogenesis of Graves’ orbitopathy Yue Wang1,2,3,4, Ziyi Chen 1, Tingjie Wang1,2, Hui Guo1, Yufeng Liu2,3,5, Ningxin Dang3, Shiqian Hu1, Liping Wu1, Chengsheng Zhang4,6,KaiYe2,3,7 and Bingyin Shi1 Graves’ orbitopathy (GO), the most severe manifestation of Graves’ hyperthyroidism (GH), is an autoimmune-mediated inflammatory disorder, and treatments often exhibit a low efficacy. CD4+ T cells have been reported to play vital roles in GO progression. To explore the pathogenic CD4+ T cell types that drive GO progression, we applied single-cell RNA sequencing (scRNA-Seq), T cell receptor sequencing (TCR-Seq), flow cytometry, immunofluorescence and mixed lymphocyte reaction (MLR) assays to evaluate CD4+ T cells from GO and GH patients. scRNA-Seq revealed the novel GO-specific cell type CD4+ cytotoxic T lymphocytes (CTLs), which are characterized by chemotactic and inflammatory features. The clonal expansion of this CD4+ CTL population, as demonstrated by TCR-Seq, along with their strong cytotoxic response to autoantigens, localization in orbital sites, and potential relationship with disease relapse provide strong evidence for the pathogenic roles of GZMB and IFN-γ-secreting CD4+ CTLs in GO. Therefore, cytotoxic pathways may become potential therapeutic targets for GO. 1234567890();,: Keywords: Graves’ orbitopathy; single-cell RNA sequencing; CD4+ cytotoxic T lymphocytes Cellular & Molecular Immunology
    [Show full text]
  • Understanding the Immune System: How It Works
    Understanding the Immune System How It Works U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH National Institute of Allergy and Infectious Diseases National Cancer Institute Understanding the Immune System How It Works U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH National Institute of Allergy and Infectious Diseases National Cancer Institute NIH Publication No. 03-5423 September 2003 www.niaid.nih.gov www.nci.nih.gov Contents 1 Introduction 2 Self and Nonself 3 The Structure of the Immune System 7 Immune Cells and Their Products 19 Mounting an Immune Response 24 Immunity: Natural and Acquired 28 Disorders of the Immune System 34 Immunology and Transplants 36 Immunity and Cancer 39 The Immune System and the Nervous System 40 Frontiers in Immunology 45 Summary 47 Glossary Introduction he immune system is a network of Tcells, tissues*, and organs that work together to defend the body against attacks by “foreign” invaders. These are primarily microbes (germs)—tiny, infection-causing Bacteria: organisms such as bacteria, viruses, streptococci parasites, and fungi. Because the human body provides an ideal environment for many microbes, they try to break in. It is the immune system’s job to keep them out or, failing that, to seek out and destroy them. Virus: When the immune system hits the wrong herpes virus target or is crippled, however, it can unleash a torrent of diseases, including allergy, arthritis, or AIDS. The immune system is amazingly complex. It can recognize and remember millions of Parasite: different enemies, and it can produce schistosome secretions and cells to match up with and wipe out each one of them.
    [Show full text]
  • Late Stages of T Cell Maturation in the Thymus
    ARTICLES Late stages of T cell maturation in the thymus involve NF-B and tonic type I interferon signaling Yan Xing, Xiaodan Wang, Stephen C Jameson & Kristin A Hogquist Positive selection occurs in the thymic cortex, but critical maturation events occur later in the medulla. Here we defined the precise stage at which T cells acquired competence to proliferate and emigrate. Transcriptome analysis of late gene changes suggested roles for the transcription factor NF-B and interferon signaling. Mice lacking the inhibitor of NF-B (IB) kinase (IKK) kinase TAK1 underwent normal positive selection but exhibited a specific block in functional maturation. NF-B signaling provided protection from death mediated by the cytokine TNF and was required for proliferation and emigration. The interferon signature was independent of NF-B; however, thymocytes deficient in the interferon- (IFN-) receptor IFN-R showed reduced expression of the transcription factor STAT1 and phenotypic abnormality but were able to proliferate. Thus, both NF-B and tonic interferon signals are involved in the final maturation of thymocytes into naive T cells. T cell development occurs in the thymus, which provides a unique reside predominantly in the medulla; however, not all SP thymocytes microenvironment and presents ligands consisting of self peptide and are equivalent. major histocompatibility complex (MHC) molecules to T cell anti- CD24hiQa2lo SP thymocytes have been defined as ‘semi-mature’ gen receptors (TCRs). In the cortex of the thymus, low-affinity TCR and have been shown to be susceptible to apoptosis when triggered interactions initiate positive selection signals in CD4+CD8+ double- through the TCR6.
    [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]
  • Download Helper and Cytotoxic T Cells.Pdf
    Category: Cells Helper and Cytotoxic T cells Original author: Tracy Hussell, University of Manchester, UK UpdatedMelissa Bedard, by: Hannah MRC Jeffery,Human Immunology University of Unit, Birmingham University of Oxford T cells are so called because they are predominantly produced in the thymus. They recognise foreign particles (antigen) by a surface expressed, highly variable, T cell receptor (TCR). There are two major types of T cells: the helper T cell and the cytotoxic T cell. As the names suggest helper T cells ‘help’ other cells of the immune system, whilst cytotoxic T cells kill virally infected cells and tumours. Unlike antibody, the TCR cannot bind antigen directly. Instead it needs to have broken-down peptides of the antigen ‘presented’ to it by an antigen presenting cell (APC). The molecules on the APC that present the antigen are called major histocompatibility complexes (MHC). There are two types of MHC: MHC class I and MHC class II. MHC class I presents to cytotoxic T cells; MHC class II presents to helper T cells. The binding of the TCR to the MHC molecule containing the antigen peptide is a little unstable and so co-receptors are required. The CD4 co-receptor (left image, below) is expressed by helper T cells and the CD8 co-receptor (right image, below) by cytotoxic T cells. Although most T cells express either CD4 or CD8, some express both and proportion do not express either (“double negative” (DN)). Most T cells are defined as CD4 or CD8 but some are classified into additional types such as invariant Natural Killer T cells (iNKT), and Mucosal Associated Invariant T cells (MAIT) The TCR is made up of multiple chains to assist the transmission of the signal to the T cell.
    [Show full text]
  • Cross-Tissue Immune Cell Analysis Reveals Tissue-Specific Adaptations and Clonal Architecture 2 Across the Human Body
    bioRxiv preprint doi: https://doi.org/10.1101/2021.04.28.441762; this version posted April 28, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. 1 Cross-tissue immune cell analysis reveals tissue-specific adaptations and clonal architecture 2 across the human body 3 Authors: 4 Domínguez Conde C1, *, Gomes T 1,*, Jarvis LB2, *, Xu C 1,*, Howlett SK 2, Rainbow DB 2, Suchanek O3 , 5 King HW 4, Mamanova L 1, Polanski K 1, Huang N1 , Fasouli E 1, Mahbubani KT 5, Prete M 1, Campos L 1,6, 6 Mousa HS 2, Needham EJ 2, Pritchard S 1,, Li T 1,, Elmentaite R 1,, Park J 1,, Menon DK 7, Bayraktar OA 1, 7 James LK 4, Meyer KB 1,, Clatworthy MR 1,3, Saeb-Parsy K 5,#, Jones JL 2, #, Teichmann SA 1,8, # 8 Affiliations: 9 1. Wellcome Sanger Institute, Cambridge, UK 10 2. Department of Clinical Neurosciences, University of Cambridge 11 3. Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK 12 4. Centre for Immunobiology, Blizard Institute, Queen Mary University of London, London, UK 13 5. Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research 14 Centre, Cambridge, UK 15 6. West Suffolk Hospital NHS Trust, Bury Saint Edmunds, UK 16 7. Department of Anaesthesia, University of Cambridge, Cambridge, UK 17 8. Theory of Condensed Matter, Cavendish Laboratory, Department of Physics, University of 18 Cambridge, Cambridge, UK 19 *Co-first authors 20 #Corresponding authors 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.04.28.441762; this version posted April 28, 2021.
    [Show full text]
  • Peptide-Induced Positive Selection of TCR Transgenic Thymocytes in a Coreceptor-Independent Manner
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Immunity, Vol. 6, 643±653, May, 1997, Copyright 1997 by Cell Press Peptide-Induced Positive Selection of TCR Transgenic Thymocytes in a Coreceptor-Independent Manner Eric Sebzda,* Mabel Choi,* Wai Ping Fung-Leung,² of the TCR and coreceptor to an MHC molecule conveys Tak W. Mak,*³ and Pamela S. Ohashi* lck to other kinases associated with the TCR complex, *Ontario Cancer Institute ultimately leading to downstream signaling. However, Departments of Medical Biophysics TCR transgenic mice expressing mutant CD8 molecules and Immunology that are unable to associate with lck are still able to Toronto, Ontario M5G 2M9 undergo thymocyte selection (Chan et al., 1993), sug- Canada gesting that CD8±lck interactions are not essential for ² R. W. Johnson Pharmaceutical T cell maturation. Similar results were obtained using Research Institute mutant CD4 molecules (Killeen and Littman, 1993). Addi- 3535 General Atomics Ct. tional experiments using TCR transgenic mice lacking San Diego, California 92121 the CD8a cytoplasmic domain have shown a defect in ³ Amgen Institute MHC class I±restricted positive selection, suggesting 620 University Ave. that an intracellular portion of CD8a is involved in thymo- Toronto, Ontario M5G 2C1 cyte development (Fung-Leung et al., 1993). Recent Canada work has also implicated the CD8b chain in signaling during T cell maturation (Crooks and Littman, 1994; Fung-Leung et al., 1994; Itano et al., 1994a; Nakayama Summary et al., 1994). Therefore, the exact function of CD8 during thymocyte selection remains unresolved. In addition to T cell receptor (TCR) transgenic thymocytes specific a potential role in signaling, experiments have demon- for the LCMV gp peptide are normally positively se- strated that coreceptors contribute to thymocyte± lected to the CD8 lineage.
    [Show full text]
  • T Cells by Regulatory T Cells + CD8 Differential Suppression of Tumor
    Differential Suppression of Tumor-Specific CD8 + T Cells by Regulatory T Cells Edward James, Alex Yeh, Cathy King, Firouzeh Korangy, Ian Bailey, Denise S. Boulanger, Benoît J. Van den Eynde, This information is current as Nicholas Murray and Tim J. Elliott of October 2, 2021. J Immunol 2010; 185:5048-5055; Prepublished online 4 October 2010; doi: 10.4049/jimmunol.1000134 http://www.jimmunol.org/content/185/9/5048 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2010/10/04/jimmunol.100013 Material 4.DC1 References This article cites 42 articles, 19 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/185/9/5048.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 2, 2021 • Fast Publication! 4 weeks from acceptance to publication *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 Differential Suppression of Tumor-Specific CD8+ T Cells by Regulatory T Cells Edward James,* Alex Yeh,*,1 Cathy King,* Firouzeh Korangy,† Ian Bailey,* Denise S.
    [Show full text]
  • Specific Cytotoxic T Cells Eliminate Cells Producing Neutralizing
    LETTERS TO NATURE Specific cytotoxic T cells a eliminate cells producing neutralizing antibodies 0 oi Oliver Planz, Peter Seiler, Hans Hengartner g b & Rolf M. Zinkernagel E ai Institute for Experimental Immunology, Department of Pathology, C. University of Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland :;::;i "'2 IN medically important infections with cytopathic viruses, neu­ > tralizing antibodies are generated within 6-14 days. In contrast, such protective antibodies appear late (50-150 days) after infec­ tion with immunodeficiency virus (HIV) and hepatitis B virus (HBV) in humans, or lymphocytic choriomeningitis virus 2 (LCMV) in mice1-6. However, during these infections, non­ <1.7-ce.--r---+---+-,i,-c'-"9--+------+-- neutralizing antibodies appear much earlier2·6•7• It has been o 5 101520 40 60 80 proposed that T cells suppress antibody responses generally Time (days) and against viruses in vitro 6·S-10• Here we show that the suppres­ sion of neutralizing-antibody responses in LCMV infections in FIG. 1 Kinetics of neutralizing and non-neutralizing antibody responses to mice is due to selective infection of neutralizing-antibody­ LCMV. a, BALB/c mice were infected i.v. with 102 PFU of LCMV-WE. Virus producing B cells by this non-cytopathic virus, and their sub­ titre ( •) in the blood of these mice is usually not detectable. Nucleoprotein­ sequent destruction by virus-specific cytotoxic T cells. Such specitic antibodies (A) appear between days 6 and 8 after infection and stay specific B-cell elimination that leads to a delay in neutralizing­ at a constant level during the whole observation period; the cross in antibody production could help to establish persistent virus parentheses indicates that only 20% of BALB/c mice infected with infections by non-cytopathic viruses.
    [Show full text]
  • CD8 T Cell Differentiation During Immune Responses Sara Sofia De Campos Pereira Lemos
    CD8 T cell differentiation during immune responses Sara Sofia de Campos Pereira Lemos To cite this version: Sara Sofia de Campos Pereira Lemos. CD8 T cell differentiation during immune responses. Immunol- ogy. Université René Descartes - Paris V, 2014. English. NNT : 2014PA05T009. tel-01059806 HAL Id: tel-01059806 https://tel.archives-ouvertes.fr/tel-01059806 Submitted on 2 Sep 2014 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITÉ PARIS DESCARTES FACULTÉ DE MEDECINE-site Necker INSERM U1020 (ex U591) _______________________________________________________________________ THÈSE Pour obtenir le grade de DOCTEUR Sciences de la Vie et de la Santé Discipline: Immunologie École Doctoral: Gc2iD Présentée et soutenue publiquement par Sara Sofia de Campos Pereira Lemos Le 23 Mai 2014 CD8 T cell differentiation during immune responses Jury: Dr. Jacqueline MARVEL Rapporteur Dr. Sylvie GUERDER Rapporteur Dr. Jérôme DELON Examinateur Dr. Nicolas BLANCHARD Examinateur Dr. Benedita ROCHA Directeur de these 1 To a wonderful person, an extraordinary woman and an amazing mother... my mother, Arlete Pereira “The first precept was never to accept a thing as true until I knew it as such without a single doubt.” René Descartes (French philosopher and scientist) “We live where no one knows the answer and the struggle is to figure out the question” Joshua Schimel (in “Writing Science” book).
    [Show full text]
  • Cytotoxic CD8+ T Cells in Cancer and Cancer Immunotherapy
    www.nature.com/bjc REVIEW ARTICLE Cytotoxic CD8+ T cells in cancer and cancer immunotherapy Hans Raskov 1, Adile Orhan1,2, Jan Pravsgaard Christensen3 and Ismail Gögenur1,4 The functions of, and interactions between, the innate and adaptive immune systems are vital for anticancer immunity. Cytotoxic T cells expressing cell-surface CD8 are the most powerful effectors in the anticancer immune response and form the backbone of current successful cancer immunotherapies. Immune-checkpoint inhibitors are designed to target immune-inhibitory receptors that function to regulate the immune response, whereas adoptive cell-transfer therapies use CD8+ T cells with genetically modified receptors—chimaeric antigen receptors—to specify and enhance CD8+ T-cell functionality. New generations of cytotoxic T cells with genetically modified or synthetic receptors are being developed and evaluated in clinical trials. Furthermore, combinatory regimens might optimise treatment effects and reduce adverse events. This review summarises advances in research on the most prominent immune effectors in cancer and cancer immunotherapy, cytotoxic T cells, and discusses possible implications for future cancer treatment. British Journal of Cancer (2021) 124:359–367; https://doi.org/10.1038/s41416-020-01048-4 BACKGROUND CD8+ T CELLS The natural immune response relies on the interaction of adaptive T lymphocytes effectively navigate and scan almost all parts of the and innate immunity systems and the synergy between them. The body for unwanted or foreign material; accordingly, naive and essential aspects of this response in terms of anticancer immunity effector T cells are highly skilled migrators central to immune are the surveillance, detection and destruction of neoplastic cells.
    [Show full text]