DOCSLIB.ORG

Defining the T Cell and Innate Lymphoid Cell Signature in Childhood Arthritis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Defining the T Cell and Innate Lymphoid Cell Signature in Childhood Arthritis Defining the T Cell and Innate Lymphoid Cell Signature in Childhood Arthritis Hannah R G Lom A thesis submitted for the degree of Doctor of Philosophy to University College London 2017 Infection, Inflammation and Rheumatology Section Infection, Immunity, Inflammation Programme UCL Great Ormond Street Institute of Child Health University College London Declaration I, Hannah R G Lom, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Abstract Pathogenesis of juvenile idiopathic arthritis (JIA) is linked to the IL-23/IL-17 axis. This is of particular interest as new biological drugs targeting this pathway have been developed and may prove a useful treatment. Increased IL-17+CD4+ T cells have been reported in the joints of patients with JIA, but less is known about IL-17 production from other cell types. Innate lymphoid cells (ILC) bridge innate and adaptive immune systems and are sub-divided into 3 types (1,2 and 3), which mirror CD4+T- cell subsets. This thesis aimed to investigate T cell and ILC contribution to the disease phenotype in the joints of patients with JIA. Using a combination of flow cytometry techniques along with multiplex cytokine analysis, qPCR and culture assays this study has assessed the immune phenotype of patients with JIA. Significant enrichments of IL-17A+ CD4+, CD8 and γδ T cells were observed in the synovial fluid of patients compared to blood, which correlated with disease severity. In parallel, a significant difference was seen between relative proportions and functionality of ILC subpopulations in the synovial fluid of patients compared to blood. IL17+ILC3 and IL-22+ILC3 were significantly enriched at the inflamed site. These two ILC3 populations were negatively correlated suggesting interplay between the two groups. Additionally, IL-17+ILC3 were associated with more severe disease. Further exploration of immune cells found a significant enrichment of myeloid DC (mDC), which strongly correlated with IL-22+ILC3 at the inflamed site. It was shown that synovial mDC produce retinoic acid which may contribute to skewing of ILC populations. These data suggest a strong IL-17A signature in JIA patients, which extends beyond the T cell compartment. Therefore, therapies targeting the IL-17/IL-23 axis could also attenuate ILC populations within the inflamed joint. Finally, these data suggest that IL22+ILC3 populations are induced by mDC and may be protective in disease. 3 Acknowledgements I would like to thank my Primary supervisor Professor Lucy Wedderburn, for taking a chance on me to complete this PhD. Thank you for guidance and enthusiasm throughout my PhD! Thank you for welcoming me into the Arthritis Research UK Centre for Adolescent Rheumatology, whose mission and work in the field is truly inspiring. I am so proud to have been a part of the centre from the beginning and am privileged to have worked as part of such an inclusive and committed team! I also thank my two secondary supervisors Dr Mona Bajaj- Elliott and Dr Yiannis Ioannou. I am particularly grateful to Mona for always making time to meet with me and for supporting me both technically and emotionally – I couldn’t have got through this without you! I am eternally grateful to Dr David Bending, who has been a great friend and an inspiration to me throughout my PhD. I am so lucky to have had your support and mentorship. Thank you for your continued guidance and patience over the last 4 years! Thanks also to all the members of the Wedderburn group and the 6th floor for your help and friendship and for generally being great fun. Particular thanks to the data managers for recruiting patients and collecting samples, and the healthy volunteers, patients and their parents, without whom none of this work could have been possible. Most importantly, I would like to thank my friends and family for their continued encouragement throughout. Thank you Mum for not humouring my (occasional) negativity and for many motivational pep talks. Josh and Jules, thank you for championing me over the last few years! And to my friends- thank you for picking me up when I have been down, and celebrating with me when I have succeeded. I couldn’t ask for more wonderful cheerleaders! I would like to dedicate this thesis to my Dad, whose relentless enthusiasm for the pursuit of knowledge has been a constant inspiration and has kept me focused and grounded during the course of my PhD. 4 Abbreviations AHR Aryl hydrocarbon receptor Ab Antibody aHC Adult healthy control APC Allophycocyanin APCs Antigen presenting cells AS Ankylosing spondylitis ATRA All-trans retinoic acid BV Brilliant violet CCL CC chemokine ligand CCR CC chemokine receptor CD Cluster of differentiation cHC Child healthy control cKIT Stem cell growth factor receptor CRTH2 Prostaglandin D2 receptor 2 CTL Cytotoxic T lymphocyte CTLA4 Cytotoxic T lymphocyte antigen 4 CXCL CXC chemokine ligand CXCR CXC chemokine receptor Cy Cyanine D Diversity segment encoding TCR chain DAPI 4',6-diamidino-2-phenylindole DC Dendritic cells DMSO Dimethylsulfoxide DMSO Dimethylsulphoxide EAE Experimental autoimmune encephalomyelitis EDTA Ethylenediaminetetraacetic acid EOMES Eomesodermin ERA Enthesitis-related arthritis ESR Erythrocyte sedimentation rate FACS Fluorescent activated cell sorting 5 FCS Foetal calf serum FITC Fluorescein isothiocyanate FOXP3 Forkhead box P3 g Gravity GATA3 GATA binding protein 3 GM-CSF Granulocyte-macrophage colony-stimulating factor GOSH Great Ormond Street Hospital HLA Human leukocyte antigen IBD Inflammatory bowel disease IFN Interferon IL Interleukin ILAR International league of associations for rheumatology ILC Innate lymphoid cells J Joining segment encoding TCR chain JIA Juvenile Idiopathic Arthritis KIR Killer-cell immunoglobulin-like receptor LPS Lipopolysaccharide MAMPs Microbe-associated molecular patterns mDC Myeloid dendritic cells MFI Mean fluorescence intensity MHCI Major histocompatibility complex I MHCII Major histocompatibility complex II MS Multiple sclerosis MTX Methotrexate NCR Natural cytotoxicity receptor NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells NK Natural killer NKp44 Natural cytotoxicity receptor 44 NKR-P1A Natural killer receptor protein 1A oligo Oligoarticular p Probability P/S/glu Penicillin/streptomycin/glutamine PAMPs Pathogen-associated molecular patterns 6 PB Peripheral blood PBMC Peripheral blood mononuclear cells PBS Phosphate buffered saline PCR Polymerase chain reaction pDC Plasmacytoid DC PE R-phycoerythrin PerCP Peridinin chlorophyll protein PMA Phorbol myristate acetate poly Polyarticular PRR Pattern recognition receptors PsA Psoriatic RA Retinoic acid RALDH Retinaldehyde dehydrogenase RAR Retinoic acid receptor RF Rheumatoid factor rh Recombinant human RORC Retinoic acid-related orphan nuclear hormone receptor C SF Synovial fluid SFMC Synovial fluid mononuclear cells SNP Single nucleotide polymorphisms SpA Spondyloarthritis STAT Signal transducer and activation of transcription T conv Conventional T cells T-bet T-box expressed in T cells TCR T cell receptor TE Tris-EDTA TGF Transforming growth factor Th T helper cell TLR Toll-like receptor TNF Tumour necrosis factor Treg Regulatory T cells TSDR Treg-specific demethylated region TSLP Thymic stromal lymphopoietin 7 UCLH University College Hospital London V Variable segment encoding TCR chain 8 Table of Contents Declaration ........................................................................................................ 2 Abstract ............................................................................................................. 3 Acknowledgements .......................................................................................... 4 Abbreviations .................................................................................................... 5 Table of Contents .............................................................................................. 9 List of Tables ................................................................................................... 13 List of Figures ................................................................................................. 14 1 : Introduction ............................................................................................ 18 1.1 Juvenile Idiopathic Arthritis .......................................................................... 19 1.1.1 Definition of Juvenile Idiopathic Arthritis (JIA) ............................................ 19 1.1.1.1 Classification of Enthesitis Related Arthritis (ERA JIA) ................................... 19 1.1.2 Pathogenesis of JIA ................................................................................... 21 1.1.2.1 Genetic associations ....................................................................................... 21 1.1.2.2 Immunopathology of JIA .................................................................................. 22 1.1.2.3 Pathogenesis of ERA JIA ................................................................................ 25 1.1.2.3.1 HLA-B27 mediated immunopathology of ERA JIA ................................... 25 1.1.2.3.2 Immune pathology of ERA JIA ................................................................. 26 1.1.2.3.3 Pathogenesis of adult spondyloarthropathies ........................................... 27 1.1.3 Current strategies for the treatment of JIA ................................................
Load more

Recommended publications
  • The TNF-Family Cytokine TL1A Drives IL-13-Dependent Small Intestinal Inflammation
    ARTICLES nature publishing group See ARTICLE page 186 The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation F M e y l a n 1 , 6 , Y - J S o n g 1 , 6 , I F u s s 2 , S V i l l a r r e a l 1 , E K a h l e 1 , I - J M a l m 1 , K A c h a r y a 1 , H L R a m o s 3 , L L o 4 , M M M e n t i n k - K a n e 5 , T A W y n n 5 , T - S M i g o n e 4 , W S t r o b e r 2 a n d R M S i e g e l 1 The tumor necrosis factor (TNF)-family cytokine TL1A (TNFSF15) costimulates T cells through its receptor DR3 (TNFRSF25) and is required for autoimmune pathology driven by diverse T-cell subsets. TL1A has been linked to human inflammatory bowel disease (IBD), but its pathogenic role is not known. We generated transgenic mice that constitutively express TL1A in T cells or dendritic cells. These mice spontaneously develop IL-13-dependent inflammatory small bowel pathology that strikingly resembles the intestinal response to nematode infections. These changes were dependent on the presence of a polyclonal T-cell receptor (TCR) repertoire, suggesting that they are driven by components in the intestinal flora. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) were present in increased numbers despite the fact that TL1A suppresses the generation of inducible Tregs.
    [Show full text]
  • Lymphopenia-Induced Proliferation Lymphocytes During and After
    The Journal of Immunology Effects of Increasing IL-7 Availability on Lymphocytes during and after Lymphopenia-Induced Proliferation1 Nabil Bosco,* Fabien Agene`s,* and Rhodri Ceredig2† IL-7 is critically involved in regulating peripheral T cell homeostasis. To investigate the role of IL-7 on lymphopenia-induced proliferation of polyclonal lymphocytes, we have transferred CFSE-labeled cells into a novel T-lymphopenic, IL-7-transgenic mouse line. Results obtained indicate that T and B cells do not respond in the same way to IL-7-homeostatic signals. Overex- pression of IL-7 enhances proliferation of both CD4؉ and CD8؉ T cells but with distinctly temporal effects. Expansion of naturally arising CD4؉-regulatory T cells was like that of conventional CD4؉ T cells. IL-7 had no effect on B cell proliferation. By immunohistology, transferred T cells homed to T cell areas of spleen lymphoid follicles. Increasing IL-7 availability enhanced T cell recovery by promoting cell proliferation and reducing apoptosis during early stages of lymphopenia-induced proliferation. Taken together, these results provide new insights into the pleiotropic effects of IL-7 on lymphopenia-induced T cell proliferation. The Journal of Immunology, 2005, 175: 162–170. espite declining thymic output with age, the peripheral T either IL-7-deficient or wild-type mice treated with anti-IL-7 or cell pool of an adult animal remains remarkably stable anti-IL-7R␣ mAb show that perturbation of IL-7 signals prevents D (1, 2). How the T cell pool is maintained remains a cen- the expansion of transferred T cells (1, 10).
    [Show full text]
  • Module 3: Development of Immune Cells
    NPTEL – Biotechnology – Cellular and Molecular Immunology Module 3: Development of immune cells Lecture 15: Development of Lymphocytes (Part I) Pluripotent stem cells and fetal liver are considered as hematopoietic stem cells in the body which give rise to lineages of blood cells. Hematopoietic stem cells also differentiate into B cells, T cells, and antigen presenting cells following maturation. The maturation of B cells mostly occurs in the fetal liver before birth and in the bone marrow after birth. The T cells form in the liver before birth and complete maturation in thymus after birth. The most common form of T cells i.e αβ T cells develop in the bone marrow while less common form γδ T cells develop in neonatal liver. The differentiation of B and T lymphocytes from precursor stem cells largely depends on the signals induced by the surface receptors present over the hematopoietic stem cells which induce different transcriptional factors involved in its maturation. 15.1 Differentiation of B and T lymphocytes from progenitor cells 15.1.1 B cells differentiation Pluripotent hematopoietic stem cells differentiate into B cells under the influence of transcription factors E2A, EBF, and Pax5. These transcription factor works synergistically to induce the transcription of specific genes and their recombination responsible for the development of B lymphocytes. Pluripotent hematopoietic stem cells are differentiated into Pro-B cells which give rise to follicle B cells, marginal B cells, and B-1 B cells. 15.1.2 T cell differentiation Pluripotent hematopoietic stem cells first give rise to common lymphoid progenitor cells. The common lymphoid progenitor cells can either give rise to natural killer cells or Pro-T cells under the influence of different transcriptional factors.
    [Show full text]
  • CD8 Naive T Cell Counts Decrease Progressively in HIV-Infected Adults
    CD8 naive T cell counts decrease progressively in HIV-infected adults. M Roederer, … , L A Herzenberg, L A Herzenberg J Clin Invest. 1995;95(5):2061-2066. https://doi.org/10.1172/JCI117892. Research Article We show here that CD8 naive T cells are depleted during the asymptomatic stage of HIV infection. Although overall CD8 T cell numbers are increased during this stage, the naive CD8 T cells are progressively lost and fall in parallel with overall CD4 T cell counts. In addition, we show that naive CD4 T cells are preferentially lost as total CD4 cell counts fall. These findings, presented here for adults, and in the accompanying study for children, represent the first demonstration that HIV disease involves the loss of both CD4 T cells and CD8 T cells. Furthermore, they provide a new insight into the mechanisms underlying the immunodeficiency of HIV-infected individuals, since naive T cells are required for all new T cell-mediated immune responses. Studies presented here also show that the well-known increase in total CD8 counts in most HIV-infected individuals is primarily due to an expansion of memory cells. Thus, memory CD8 T cells comprise over 80% of the T cells in PBMC from individuals with < 200 CD4/microliter, whereas they comprise roughly 15% in uninfected individuals. Since the naive and memory subsets have very different functional activities, this altered naive/memory T cell representation has significant consequences for the interpretation of data from in vitro functional studies. Find the latest version: https://jci.me/117892/pdf CD8 Naive T Cell Counts Decrease Progressively in HIV-infected Adults Mario Roederer, J.
    [Show full text]
  • Immunology 101
    Immunology 101 Justin Kline, M.D. Assistant Professor of Medicine Section of Hematology/Oncology Committee on Immunology University of Chicago Medicine Disclosures • I served as a consultant on Advisory Boards for Merck and Seattle Genetics. • I will discuss non-FDA-approved therapies for cancer 2 Outline • Innate and adaptive immune systems – brief intro • How immune responses against cancer are generated • Cancer antigens in the era of cancer exome sequencing • Dendritic cells • T cells • Cancer immune evasion • Cancer immunotherapies – brief intro 3 The immune system • Evolved to provide protection against invasive pathogens • Consists of a variety of cells and proteins whose purpose is to generate immune responses against micro-organisms • The immune system is “educated” to attack foreign invaders, but at the same time, leave healthy, self-tissues unharmed • The immune system can sometimes recognize and kill cancer cells • 2 main branches • Innate immune system – Initial responders • Adaptive immune system – Tailored attack 4 The immune system – a division of labor Innate immune system • Initial recognition of non-self (i.e. infection, cancer) • Comprised of cells (granulocytes, monocytes, dendritic cells and NK cells) and proteins (complement) • Recognizes non-self via receptors that “see” microbial structures (cell wall components, DNA, RNA) • Pattern recognition receptors (PRRs) • Necessary for priming adaptive immune responses 5 The immune system – a division of labor Adaptive immune system • Provides nearly unlimited diversity of receptors to protect the host from infection • B cells and T cells • Have unique receptors generated during development • B cells produce antibodies which help fight infection • T cells patrol for infected or cancerous cells • Recognize “foreign” or abnormal proteins on the cell surface • 100,000,000 unique T cells are present in all of us • Retains “memory” against infections and in some cases, cancer.
    [Show full text]
  • The Anatomy of T-Cell Activation and Tolerance Anna Mondino*T, Alexander Khoruts*, and Marc K
    Proc. Natl. Acad. Sci. USA Vol. 93, pp. 2245-2252, March 1996 Review The anatomy of T-cell activation and tolerance Anna Mondino*t, Alexander Khoruts*, and Marc K. Jenkins Department of Microbiology and the Center for Immunology, University of Minnesota Medical School, 420 Delaware Street S.E, Minneapolis, MN 55455 ABSTRACT The mammalian im- In recent years, it has become clear that TCR is specific for a self peptide-class I mune system must specifically recognize a full understanding of immune tolerance MHC complex) T cell that will exit the and eliminate foreign invaders but refrain cannot be achieved with reductionist in thymus and seed the secondary lymphoid from damaging the host. This task is vitro approaches that separate the individ- tissues (3, 4). In contrast, cortical CD4+ accomplished in part by the production of ual lymphocyte from its in vivo environ- CD8+ thymocytes that express TCRs that a large number of T lymphocytes, each ment. The in vivo immune response is a have no avidity for self peptide-MHC bearing a different antigen receptor to well-organized process that involves mul- complexes do not survive and die by an match the enormous variety of antigens tiple interactions of lymphocytes with each apoptotic mechanism. Cortical epithelial present in the microbial world. However, other, with bone-marrow-derived antigen- cells are essential for the process of pos- because antigen receptor diversity is gen- presenting cells (APCs), as well as with itive selection because they display the self erated by a random mechanism, the im- nonlymphoid cells and their products. The peptide-MHC complexes that are recog- mune system must tolerate the function of anatomic features that are designed to op- nized by CD4+ CD8+ thymocytes and also T lymphocytes that by chance express a timize immune tolerance toward innocuous provide essential differentiation factors self-reactive antigen receptor.
    [Show full text]
  • Vaccine Immunology Claire-Anne Siegrist
    2 Vaccine Immunology Claire-Anne Siegrist To generate vaccine-mediated protection is a complex chal- non–antigen-specifc responses possibly leading to allergy, lenge. Currently available vaccines have largely been devel- autoimmunity, or even premature death—are being raised. oped empirically, with little or no understanding of how they Certain “off-targets effects” of vaccines have also been recog- activate the immune system. Their early protective effcacy is nized and call for studies to quantify their impact and identify primarily conferred by the induction of antigen-specifc anti- the mechanisms at play. The objective of this chapter is to bodies (Box 2.1). However, there is more to antibody- extract from the complex and rapidly evolving feld of immu- mediated protection than the peak of vaccine-induced nology the main concepts that are useful to better address antibody titers. The quality of such antibodies (e.g., their these important questions. avidity, specifcity, or neutralizing capacity) has been identi- fed as a determining factor in effcacy. Long-term protection HOW DO VACCINES MEDIATE PROTECTION? requires the persistence of vaccine antibodies above protective thresholds and/or the maintenance of immune memory cells Vaccines protect by inducing effector mechanisms (cells or capable of rapid and effective reactivation with subsequent molecules) capable of rapidly controlling replicating patho- microbial exposure. The determinants of immune memory gens or inactivating their toxic components. Vaccine-induced induction, as well as the relative contribution of persisting immune effectors (Table 2.1) are essentially antibodies— antibodies and of immune memory to protection against spe- produced by B lymphocytes—capable of binding specifcally cifc diseases, are essential parameters of long-term vaccine to a toxin or a pathogen.2 Other potential effectors are cyto- effcacy.
    [Show full text]
  • Naive and Memory T Cells Induce Different Types of Graft-Versus-Host Disease1
    The Journal of Immunology Naive and Memory T Cells Induce Different Types of Graft-versus-Host Disease1 Suparna Dutt,* Diane Tseng,* Joerg Ermann,* Tracy I. George,† Yin Ping Liu,* Corrine R. Davis,‡ C. Garrison Fathman,* and Samuel Strober2* The goal of this study was to compare the ability of donor naive and alloantigen-primed effector memory T cells to induce graft-vs-host disease after bone marrow transplantation in MHC-mismatched irradiated host mice. Purified CD4؉ naive CD62LhighCD44low) T cells and CD4؉ effector memory (CD62LlowCD44high) T cells obtained from unprimed donors and donors) primed to host alloantigens, respectively, were injected into host mice, and the rapidity, severity, and pattern of tissue injury of graft-vs-host disease was assessed. Unexpectedly, the naive T cells induced a more acute and severe colitis than the primed memory cells. Whereas the naive T cells expressing CD62L and CCR7 lymph node homing receptors vigorously expanded in mesenteric lymph nodes and colon by day 6 after transplantation, the primed memory T cells without these receptors had 20- to 100-fold lower accumulation at this early time point. These differences were reflected in the significantly more rapid decline in survival and weight loss induced by naive T cells. The primed memory T cells had a greater capacity to induce chronic colitis and liver injury and secrete IL-2 and IFN-␥ in response to alloantigenic stimulation compared with memory T cells from unprimed donors. Never- theless, the expected increase in potency as compared with naive T cells was not observed due to differences in the pattern and kinetics of tissue injury.
    [Show full text]
  • Resting B Lymphocytes As APC for Naive T Lymphocytes: Dependence on CD40 Ligand/CD401
    Resting B Lymphocytes as APC for Naive T Lymphocytes: Dependence on CD40 Ligand/CD401 Dean E. Evans,2 Michael W. Munks, Jeffrey M. Purkerson,3 and David C. Parker4 Although resting B cells as APC are tolerogenic for naive T cells in vivo, we show here that they can provide all the costimulatory signals necessary for naive T cell proliferation in vivo and in vitro. In the absence of an activating signal through the B cell Ag receptor, T cell proliferation after Ag recognition on resting B cells depends on CD40 expression on the B cells, implying that naive T cells use the membrane-bound cytokine, CD40 ligand (CD154), to induce the costimulatory signals that they need. Induction of B7-1 (CD80) and increased or sustained expression of CD44H, ICAM-1 (CD54), and B7-2 (CD86) are dependent on the interaction of CD40 ligand with CD40. Transient expression (12 h) of B7-2 is T cell- and peptide Ag-dependent, but CD40-independent. Only sustained (>24 h) expression of B7-2 and perhaps increased expression of ICAM-1 could be shown to be functionally important in this system. T cells cultured with CD40-deficient B cells and peptide remain about as responsive as fresh naive cells upon secondary culture with whole splenic APC. Therefore, B cells, and perhaps other APC, may be tolerogenic not because they fail to provide sufficient costimulation for T cell proliferation, but because they are deficient in some later functions necessary for a productive T cell response. The Journal of Immunology, 2000, 164: 688–697. Downloaded from he outcome of the interaction between an Ag-specific B A key regulator of Ag-specific T/B cell interactions is CD40 cell and an Ag-specific T cell can be tolerance or immu- ligand (CD40L;5 CD154), the membrane-bound ligand for CD40 T nity, depending on the state of activation of the T cell and and the major mediator of contact-dependent help for B cell pro- the B cell, although the rules and the molecular interactions that liferation and differentiation in the Ab response (19, 20).
    [Show full text]
  • Memory CD4 T Cell Subsets Are Kinetically Heterogeneous
    RESEARCH ARTICLE Memory CD4 T cell subsets are kinetically heterogeneous and replenished from naive T cells at high levels Graeme Gossel1,2†§, Thea Hogan3†, Daniel Cownden1, Benedict Seddon3*‡, Andrew J Yates1*‡ 1Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary & Life Sciences University of Glasgow, Glasgow, United Kingdom; 2Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States; 3Institute of Immunity and Transplantation, University College London, London, United Kingdom Abstract Characterising the longevity of immunological memory requires establishing the rules underlying the renewal and death of peripheral T cells. However, we lack knowledge of the population structure and how self-renewal and de novo influx contribute to the maintenance of *For correspondence: benedict. memory compartments. Here, we characterise the kinetics and structure of murine CD4 T cell [email protected] (BS); andrew. [email protected] (AJY) memory subsets by measuring the rates of influx of new cells and using detailed timecourses of DNA labelling that also distinguish the behaviour of recently divided and quiescent cells. We find † These authors contributed that both effector and central memory CD4 T cells comprise subpopulations with highly divergent equally to this work rates of turnover, and show that inflows of new cells sourced from the naive pool strongly impact ‡ These authors also contributed estimates of memory cell lifetimes and division rates. We also demonstrate that the maintenance of equally to this work CD4 T cell memory subsets in healthy mice is unexpectedly and strikingly reliant on this Present address: §Department replenishment. of Physics and Astronomy, DOI: 10.7554/eLife.23013.001 Hunter College, City University of New York, New York, United States Competing interests: The authors declare that no Introduction competing interests exist.
    [Show full text]
  • Human T Cell Memory: a Dynamic View
    vaccines Review Human T Cell Memory: A Dynamic View Derek C. Macallan 1,2,*, José A. M. Borghans 3 and Becca Asquith 4 1 Institute for Infection & Immunity, St George’s, University of London, Cranmer Terrace, London SW17 0RE, UK 2 St George’s University Hospitals NHS Foundation Trust, Blackshaw Road, London SW17 0QT, UK 3 Laboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht, P.O. Box 85090, 3508 AB Utrecht, The Netherlands; [email protected] 4 Department of Medicine, Imperial College London W2 1PG, UK; [email protected] * Correspondence: [email protected]; Tel.: +44-208-725-0283; Fax: +44-208-725-3487 Academic Editor: Stephen Todryk Received: 18 July 2016; Accepted: 17 January 2017; Published: 4 February 2017 Abstract: Long-term T cell-mediated protection depends upon the formation of a pool of memory cells to protect against future pathogen challenge. In this review we argue that looking at T cell memory from a dynamic viewpoint can help in understanding how memory populations are maintained following pathogen exposure or vaccination. For example, a dynamic view resolves the apparent paradox between the relatively short lifespans of individual memory cells and very long-lived immunological memory by focussing on the persistence of clonal populations, rather than individual cells. Clonal survival is achieved by balancing proliferation, death and differentiation rates within and between identifiable phenotypic pools; such pools correspond broadly to sequential stages in the linear differentiation pathway. Each pool has its own characteristic kinetics, but only when considered as a population; single cells exhibit considerable heterogeneity.
    [Show full text]
  • Different Subsets of T Cells, Memory, Effector Functions, and CAR-T Immunotherapy
    cancers Review Different Subsets of T Cells, Memory, Effector Functions, and CAR-T Immunotherapy Vita Golubovskaya * and Lijun Wu * Promab Biotechnologies, 2600 Hilltop Drive, Suite 320, Richmond, CA 94803, USA * Correspondence: [email protected] (V.G.); [email protected] (L.W.); Tel.: +1-352-262-4846 (V.G.); +1-510-529-3021 (L.W.); Fax: +1-510-740-3625 (V.G. & L.W.) Academic Editor: Samuel C. Mok Received: 8 January 2016; Accepted: 10 March 2016; Published: 15 March 2016 Abstract: This review is focused on different subsets of T cells: CD4 and CD8, memory and effector functions, and their role in CAR-T therapy—-a cellular adoptive immunotherapy with T cells expressing chimeric antigen receptor. The CAR-T cells recognize tumor antigens and induce cytotoxic activities against tumor cells. Recently, differences in T cell functions and the role of memory and effector T cells were shown to be important in CAR-T cell immunotherapy. The CD4+ subsets (Th1, Th2, Th9, Th17, Th22, Treg, and Tfh) and CD8+ memory and effector subsets differ in extra-cellular (CD25, CD45RO, CD45RA, CCR-7, L-Selectin [CD62L], etc.); intracellular markers (FOXP3); epigenetic and genetic programs; and metabolic pathways (catabolic or anabolic); and these differences can be modulated to improve CAR-T therapy. In addition, CD4+ Treg cells suppress the efficacy of CAR-T cell therapy, and different approaches to overcome this suppression are discussed in this review. Thus, next-generation CAR-T immunotherapy can be improved, based on our knowledge of T cell subsets functions, differentiation, proliferation, and signaling pathways to generate more active CAR-T cells against tumors.
    [Show full text]