Lymphotactin Mediates Antiviral T Cell Trafficking Within

Total Page:16

File Type:pdf, Size:1020Kb

Lymphotactin Mediates Antiviral T Cell Trafficking Within LYMPHOTACTIN MEDIATES ANTIVIRAL T CELL TRAFFICKING WITHIN THE CENTRAL NERVOUS SYSTEM DURING WEST NILE VIRUS ENCEPHALITIS A Thesis Presented to the Faculty of California State Polytechnic University, Pomona In Partial Fulfillment Of the Requirements for the Degree Master of Science In Biological Sciences By Sharese Tronti 2019 SIGNATURE PAGE THESIS: LYMPHOTACTIN MEDIATES ANTIVIRAL T CELL TRAFFICKING WITHIN THE CENTRAL NERVOUS SYSTEM DURING WEST NILE VIRUS ENCEPHALITIS AUTHOR: Sharese Tronti DATE SUBMITTED: Spring 2019 Department of Biological Sciences Dr. Douglas Durrant Thesis Committee Chair Biological Sciences Dr. Andrew Steele Biological Sciences Dr. Jamie Snyder Biological Science ii ABSTRACT West Nile Virus (WNV), a neurotropic flavivirus, can cause neuroinvasive disease in humans. After peripheral infection, WNV is able to enter the central nervous system (CNS) and infect neurons causing neuronal injury and inflammation that potentially may result in fatality. In order to restrict viral replication and pathogenesis within the CNS during WNV encephalitis, virus-specific CD8+ T cells are critically dependent on dendritic cell (DC) mediated reactivation at this site. However, the mechanism by which DCs are recruited to the brain to ensure their interaction with infiltrating virus-specific CD8+ T cells remains unknown. Previous studies have demonstrated that, upon activation, CD8+ T cells rapidly produce the chemokine lymphotactin when activated. The receptor for lymphotactin, XCR1, is exclusively expressed on a subset of DCs, CD8+ DCs, which have been shown to be essential in establishing protective peripheral immunity against viruses and intracellular bacteria. In this study, we show that lymphotactin regulates the CNS entry of T lymphocytes, potentially promoting virologic control within the CNS and limiting neuronal cell death. Although, no apparent differences were obtained in survival and clinical disease progression, WNV-infected mice, that had been treated with an XCL1-neutralizing antibody, displayed increased parenchymal localization of T cells within the brain compared to control mice. These data indicate that lymphotactin contributes to stabilizing the cellular interactions between infiltrating T cells and CNS-localized DCs with may impart protective CNS inflammation by regulating the parenchymal entry of T cells during WNV encephalitis. iii Table of Contents Signature Page ………………………………………………………………………… ii Abstract ………………………………………………………………………………... iii List of Tables ………………………………………………………………………….. vi List of Figures …………………………………………………………………………. vii Introduction ……………………………………………………………………………. 1 West Nile Virus ………………………………………………………………………… 1 West Nile Virus Neuroinvasive Disease ……………………………………………..3 West Nile Virus Immunity ……………………………………………………………. 5 Dendititic Cells and Lymphotactin …………………………………………………. 8 Hypothesis ……………………………………………………………………………... 10 Materials and Methods ………………………………………………………………… 12 Ethics Statement ……………………………………………………………………….. 12 Virus …………………………………………………………………………………….. 12 Mouse Infection ……………………………………………………………………….. 12 Lymphotactin Neutralization ………………………………………………………… 13 Tissue Collection and Preparation …………………………………………………. 13 RNA Isolation and qRT-PCR ………………………………………………………… 13 Lymphotactin Protein Analysis ……………………………………………………… 14 Immunohistochemistry ……………………………………………………………….. 14 Statistical Analysis ……………………………………………………….…………… 15 Results …………………………………………………………………………………. 16 Lymphotactin Expression and its Protective Role During WNV Neuroinvasive iv Disease ……………………………………………………………………………...….. 16 Lymphotactin Is Effectively Neutralized In Peripheral Tissues via Anti-XCL1.. 18 Lymphotactin Plays a Role in Control of WNV Burden within the CNS .……... 19 Lymphotactin Plays a Protective Role Against Virus-Associated Neuronal Cell Death ………………………………………………………………………………. ..… 19 Lymphotactin Impacts the Localization of T cells During WNV Encephalitis… 20 Discussion …………………………………………………………………………….. 31 References …………………………………………………………………………….. 37 v LIST OF TABLES Table 1: Health Status Assessment Results on day 5. ………………………………….22 vi LIST OF FIGURES Figure 1: CD8+ T cells arrested within the perivascular space without antigen- recognition……………………………………………………………………………… 23 Figure 2: Lymphotactin levels during WNV encephalitis …………………………….. 24 Figure 3: Percent of weight change in mice from days -1 to 5 post West Nile infection..25 Figure 4: Percent of survival to day 5 post West Nile infection ………………………. 25 Figure 5: Lymphotactin is effectively neutralized in peripheral tissues via anti- XCL1…………………………………………………………………………………… 26 Figure 6: Lymphotactin plays a role in control of WNV burden within the CNS. ...….. 27 Figure 7: Lymphotactin plays a protective role against virus-associated neuronal cell death ……………………………………………………………………………….. ….. 28 Figure 8: Lymphotactin impacts the localization of T cells during WNV encephalitis.. 29 Figure 9: Lymphotactin-mediated recruitment of DCs to the perivascular space ……. 30 vii INTRODUCTION West Nile Virus (WNV), a mosquito-borne neurotropic flavivirus, has emerged globally as a significant cause of viral encephalitis and meningitis. Due to human and environmental factors, WNV has disseminated throughout the Western world and continues to spread causing increased outbreaks and WNV disease in humans. Currently, there remains no vaccine or specific therapy approved to treat or prevent WNV infection. Due to the fact that WNV continues to pose a significant public health risk, there remains a pressing need to understand the viral and host factors that determine viral pathogenesis and outcome of WNV infection. West Nile Virus West Nile Virus (WNV) is spread by the bite of a mosquito and is maintained in a cycle between birds and mosquitoes, but can also be spread to humans and other mammals which serve as dead-end hosts (Lim et al, 2011). WNV is endemic in parts of Africa, Asia, Europe, and the Middle East and since its emergence in the United States in 1999, reports have been made of its presence in the Caribbean, Mexico, and South America (Dauphin et al, 2004). According to the CDC, there were 2544 cases of WNV infections in the US in 2018, 1594 of them being neuroinvasive resulting in 137 deaths (CDC, 2019). West Nile infection in humans can range from a flu-like disease to encephalitis, acute flaccid paralysis, and death (Cho and Diamond, 2012). Prevention of WNV infection is limited to the prevention of mosquito bites, including insect repellent, long clothing, and mosquito population control. There is currently no specific therapy or vaccine approved for human use (DeFilette et al, 2012). WNV is a neurotropic flavivirus with a single-stranded positive-sense RNA 1 genome (Donadieu et al, 2013). The ssrRNA genome encodes for three structural proteins; including, the capsid protein (C), the envelope protein (E), and the membrane protein (prM), and at least seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5) (Kramer et al, 2007). Upon infection, WNV initially targets primarily dendritic cells and endothelial cells as well as macrophages and monocytes (Pierson et al, 2013). Viral dissemination occurs during the lytic infection of these cells, which leads to increased viremia. Although, the receptor necessary for virion attachment and entry have not yet been fully identified, it is known that WNV gains entry into cells by receptor-mediated endocytosis via clatherin-coated pits and delivery of the RNA genome occurs following membrane fusion within the early endosome (Chambers et al, 1990). After, the viral genome is then released into the cytoplasm where translation of the nonstructural protein occurs as well as RNA synthesis. The viral RNA then associates with the endoplasmic reticulum, with the aid of NS2A, NS2B, NS4A, and NS4B, where replication of the viral genome RNA occurs (Brinton, 2014). Genomic viral RNA is packaged into progeny virions which then bud into the endoplasmic reticulum to form enveloped immature virions. Further maturation occurs in the trans Golgi network, where the NS3-NS2B complex is required for efficient polyprotein processing. Finally, the virions are secreted into the extracellular space by exocytosis. West Nile virions begin to be released from infected cells 8 hours after infection and peak around 24 hours (Cho and Diamond, 2012). WNV is transferred after a mosquito intradermally inoculates a subject. The virus initially replicates in keratinocytes, newly recruited neutrophils, and skin dendritic cells (Langerhans cells) which then migrate to the regional lymph nodes and the bloodstream 2 (Lim et al, 2011). This leads to primary viremia during days 3-4 after infection which can then lead to infection of the kidneys, liver, and spleen (Samuel and Diamond, 2006). In the periphery, infection is countered by the development of an early immune response including type I and II IFN production as was as the effector functions of innate immune cells such as IgM secreting B cells, NK cells, neutrophils, and macrophages (Cho and Diamond, 2012). Within the draining lymph nodes, viral antigen presentation to naïve T cells, complement activation, and antiviral cytokine and chemokine expression occurs. By the end of the first week post-infection, WNV is cleared from the peripheral organs and infection of the central nervous system (CNS) can be observed starting on day five after infection, with the probability of neuroinvasion correlated with the duration and level of viremia (Cho and Diamond, 2012). The mechanisms in which WNV enters
Recommended publications
  • Rescuing Functional T Cells Induced by Growth Factor Deprivation, CCL2 Inhibits the Apoptosis Program
    CCL2 Inhibits the Apoptosis Program Induced by Growth Factor Deprivation, Rescuing Functional T Cells This information is current as Eva Diaz-Guerra, Rolando Vernal, M. Julieta del Prete, of September 24, 2021. Augusto Silva and Jose A. Garcia-Sanz J Immunol 2007; 179:7352-7357; ; doi: 10.4049/jimmunol.179.11.7352 http://www.jimmunol.org/content/179/11/7352 Downloaded from References This article cites 41 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/179/11/7352.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 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology CCL2 Inhibits the Apoptosis Program Induced by Growth Factor Deprivation, Rescuing Functional T Cells1 Eva Diaz-Guerra,2 Rolando Vernal,2 M. Julieta del Prete,2 Augusto Silva, and Jose A. Garcia-Sanz3 The precise mechanisms involved in the switch between the clonal expansion and contraction phases of a CD8؉ T cell response remain to be fully elucidated.
    [Show full text]
  • Interleukin-15-Mediated Immunotoxicity and Exacerbation of Sepsis
    INTERLEUKIN-15-MEDIATED IMMUNOTOXICITY AND EXACERBATION OF SEPSIS: ROLE OF NATURAL KILLER CELLS AND INTERFERON γ By Yin Guo Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Microbiology and Immunology December 2016 Nashville, Tennessee Approved Luc Van Kaer, Ph.D. Stokes Peebles, M.D. Lorraine Ware, M.D. Daniel Moore, M.D., Ph.D. Edward Sherwood, M.D, Ph.D. i Copyright © 2016 by Yin Guo All Rights Reserved ii ACKNOWLEDGEMENTS I would like to thank my thesis mentor, Dr. Edward Sherwood for his tremendous instruction and support during my entire Ph.D. training course. I joined Dr. Sherwood’s lab in the department of Microbiology and Immunology of University of Texas Medical Branch (UTMB) at Galveston in 2011. I appreciated the offer Dr. Sherwood provided to move to Vanderbilt University together. During the new lab setup period, he gave me a lot of encouragement about going out to meet students and professors at the Pathology, Microbiology and Immunology Department. From making new friends in our department, I started to know a lot of useful information and resources about how to adapt to new life in Nashville and how to prepare for the qualifying exam. Dr. Sherwood is a highly responsible and enthusiastic mentor although he has busy medical practice in the operating room and needs to write many grants. I have to say, he is the most diligent person I have seen in the world. It is amazing to me that he never seems to be exhausted or desensitized with reviewing our papers, reading papers, writing grants, and discussing data and new ideas.
    [Show full text]
  • Metamorphic Protein Folding Encodes Multiple Anti-Candida Mechanisms in XCL1
    pathogens Article Metamorphic Protein Folding Encodes Multiple Anti-Candida Mechanisms in XCL1 Acacia F. Dishman 1,2,†, Jie He 3,†, Brian F. Volkman 1,* and Anna R. Huppler 3,* 1 Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA; [email protected] 2 Medical Scientist Training Program, Medical College of Wisconsin, Milwaukee, WI 53226, USA 3 Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA; [email protected] * Correspondence: [email protected] (B.F.V.); [email protected] (A.R.H.) † These authors contributed equally. Abstract: Candida species cause serious infections requiring prolonged and sometimes toxic therapy. Antimicrobial proteins, such as chemokines, hold great interest as potential additions to the small number of available antifungal drugs. Metamorphic proteins reversibly switch between multiple different folded structures. XCL1 is a metamorphic, antimicrobial chemokine that interconverts between the conserved chemokine fold (an α–β monomer) and an alternate fold (an all-β dimer). Previous work has shown that human XCL1 kills C. albicans but has not assessed whether one or both XCL1 folds perform this activity. Here, we use structurally locked engineered XCL1 variants and Candida killing assays, adenylate kinase release assays, and propidium iodide uptake assays to demonstrate that both XCL1 folds kill Candida, but they do so via different mechanisms. Our results suggest that the alternate fold kills via membrane disruption, consistent with previous work, and the chemokine fold does not. XCL1 fold-switching thus provides a mechanism to regulate Citation: Dishman, A.F.; He, J.; the XCL1 mode of antifungal killing, which could protect surrounding tissue from damage associ- Volkman, B.F.; Huppler, A.R.
    [Show full text]
  • Single-Cell Landscape of Bronchoalveolar Immune Cells in Patients with COVID-19
    BRIEF COMMUNICATION https://doi.org/10.1038/s41591-020-0901-9 Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19 Mingfeng Liao1,6, Yang Liu1,6, Jing Yuan2,6, Yanling Wen1, Gang Xu1, Juanjuan Zhao1, Lin Cheng1, Jinxiu Li2, Xin Wang1, Fuxiang Wang2, Lei Liu1,3 ✉ , Ido Amit 4 ✉ , Shuye Zhang 5 ✉ and Zheng Zhang 1,3 ✉ Respiratory immune characteristics associated with The macrophage compartments differed largely in both compo- Coronavirus Disease 2019 (COVID-19) severity are cur- sition and expression of FCN1, SPP1 and FABP4 in different cell rently unclear. We characterized bronchoalveolar lavage fluid groups (Fig. 1c and Extended Data Fig. 2d). FABP4 was prefer- immune cells from patients with varying severity of COVID-19 entially expressed by controls and patients with moderate infec- and from healthy people by using single-cell RNA sequencing. tion, while FCN1 and SPP1 were highly expressed by patients Proinflammatory monocyte-derived macrophages were abun- with severe/critical infection (Fig. 1d). We conducted differen- dant in the bronchoalveolar lavage fluid from patients with tially expressed gene (DEG) analysis (Extended Data Fig. 2e), gene severe COVID-9. Moderate cases were characterized by the ontology (GO) analysis and gene set enrichment analysis (GSEA) presence of highly clonally expanded CD8+ T cells. This atlas (Extended Data Fig. 2f) between cell groups. Group 1 expressed of the bronchoalveolar immune microenvironment suggests the peripheral monocyte-like markers S100A8, FCN1 and CD14, potential mechanisms underlying pathogenesis and recovery and group 2 expressed high levels of the chemokines CCL2, CCL3, in COVID-19. CXCL10 and other genes.
    [Show full text]
  • COMPREHENSIVE INVITED REVIEW Chemokines and Their Receptors
    COMPREHENSIVE INVITED REVIEW Chemokines and Their Receptors Are Key Players in the Orchestra That Regulates Wound Healing Manuela Martins-Green,* Melissa Petreaca, and Lei Wang Department of Cell Biology and Neuroscience, University of California, Riverside, California. Significance: Normal wound healing progresses through a series of over- lapping phases, all of which are coordinated and regulated by a variety of molecules, including chemokines. Because these regulatory molecules play roles during the various stages of healing, alterations in their presence or function can lead to dysregulation of the wound-healing process, potentially leading to the development of chronic, nonhealing wounds. Recent Advances: A discovery that chemokines participate in a variety of disease conditions has propelled the study of these proteins to a level that potentially could lead to new avenues to treat disease. Their small size, ex- posed termini, and the fact that their only modifications are two disulfide Manuela Martins-Green, PhD bonds make them excellent targets for manipulation. In addition, because they bind to G-protein-coupled receptors (GPCRs), they are highly amenable to Submitted for publication January 9, 2013. *Correspondence: Department of Cell Biology pharmacological modulation. and Neuroscience, University of California, Riv- Critical Issues: Chemokines are multifunctional, and in many situations, their erside, Biological Sciences Building, 900 Uni- functions are highly dependent on the microenvironment. Moreover, each versity Ave., Riverside, CA 92521 (email: [email protected]). specific chemokine can bind to several GPCRs to stimulate the function, and both can function as monomers, homodimers, heterodimers, and even oligo- mers. Activation of one receptor by any single chemokine can lead to desen- Abbreviations sitization of other chemokine receptors, or even other GPCRs in the same cell, and Acronyms with implications for how these proteins or their receptors could be used to Ang-2 = angiopoietin-2 manipulate function.
    [Show full text]
  • Aire-Dependent Production of XCL1 Mediates Medullary Accumulation of Thymic Dendritic Cells and Contributes to Regulatory T Cell Development
    Article Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development Yu Lei,1,3 Adiratna Mat Ripen,1 Naozumi Ishimaru,2 Izumi Ohigashi,1 Takashi Nagasawa,4 Lukas T. Jeker,5 Michael R. Bösl,6 Georg A. Holländer,5 Yoshio Hayashi,2 Rene de Waal Malefyt,7 Takeshi Nitta,1 and Yousuke Takahama1 1Division of Experimental Immunology, Institute for Genome Research, 2Department of Oral Molecular Pathology, Institute of Health Biosciences, University of Tokushima, Tokushima 770-8503, Japan 3Key Laboratory of Molecular Biology for Infectious Disease of the People’s Republic of China Ministry of Education, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China 4Department of Immunobiology and Hematology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan 5Laboratory of Pediatric Immunology, Center for Biomedicine, University of Basel and The University Children’s Hospital of Basel, 4058 Basel, Switzerland 6 Transgenic Core Facility, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany 7Merck Research Laboratories, Palo Alto, CA 94304 Dendritic cells (DCs) in the thymus (tDCs) are predominantly accumulated in the medulla and contribute to the establishment of self-tolerance. However, how the medullary accu- mulation of tDCs is regulated and involved in self-tolerance is unclear. We show that the chemokine receptor XCR1 is expressed by tDCs, whereas medullary thymic epithelial cells (mTECs) express the ligand XCL1. XCL1-deficient mice are defective in the medullary accumulation of tDCs and the thymic generation of naturally occurring regulatory T cells (nT reg cells). Thymocytes from XCL1-deficient mice elicit dacryoadenitis in nude mice.
    [Show full text]
  • 359.Full.Pdf
    359 Ann Rheum Dis: first published as 10.1136/ard.2003.017566 on 26 August 2004. Downloaded from EXTENDED REPORT Increased expression of CCL18, CCL19, and CCL17 by dendritic cells from patients with rheumatoid arthritis, and regulation by Fc gamma receptors T R D J Radstake, R van der Voort, M ten Brummelhuis, M de Waal Malefijt, M Looman, C G Figdor, W B van den Berg, P Barrera, G J Adema ............................................................................................................................... Ann Rheum Dis 2005;64:359–367. doi: 10.1136/ard.2003.017566 See end of article for authors’ affiliations ....................... Background: Dendritic cells (DC) have a role in the regulation of immunity and tolerance, attracting Correspondence to: inflammatory cells by the production of various chemokines (CK). Fc gamma receptors (FccR) may be Dr T R D J Radstake, involved in regulation of the DC function. Department of Objective: To assess the expression of CK by immature (iDC) and mature DC (mDC) and its regulation by Rheumatology/Laboratory of Experimental FccR in patients with RA and healthy donors (HC). Rheumatology and Methods: Expression of CK by DC from patients with RA and from HC was determined by real time Advanced Therapeutics, quantitative PCR and ELISA. DC were derived from monocytes following standardised protocols. To study University Medical Centre the potential regulation by FccR, iDC were stimulated with immune complexes (IC) during Nijmegen, The Netherlands and lipopolysaccharide (LPS) induced maturation. The presence of CK was studied in synovial tissue from Nijmegen Centre for patients with RA, osteoarthritis, and healthy subjects by RT-PCR and immunohistochemistry. Molecular Life Sciences, Results: iDC from patients with RA had markedly increased mRNA levels of the CK CCL18 and CXCL8.
    [Show full text]
  • A Novel Α9 Integrin Ligand, XCL1/Lymphotactin, Is Involved in the Development of Murine Models of Autoimmune Diseases
    A Novel α9 Integrin Ligand, XCL1/Lymphotactin, Is Involved in the Development of Murine Models of Autoimmune Diseases This information is current as of September 25, 2021. Naoki Matsumoto, Shigeyuki Kon, Takuya Nakatsuru, Tomoe Miyashita, Kyosuke Inui, Kodai Saitoh, Yuichi Kitai, Ryuta Muromoto, Jun-ichi Kashiwakura, Toshimitsu Uede and Tadashi Matsuda J Immunol 2017; 199:82-90; Prepublished online 26 May Downloaded from 2017; doi: 10.4049/jimmunol.1601329 http://www.jimmunol.org/content/199/1/82 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2017/05/26/jimmunol.160132 Material 9.DCSupplemental References This article cites 40 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/199/1/82.full#ref-list-1 by guest on September 25, 2021 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 *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 © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology A Novel a9 Integrin Ligand, XCL1/Lymphotactin, Is Involved in the Development of Murine Models of Autoimmune Diseases Naoki Matsumoto,*,1 Shigeyuki Kon,*,†,1 Takuya Nakatsuru,* Tomoe Miyashita,* Kyosuke Inui,* Kodai Saitoh,* Yuichi Kitai,* Ryuta Muromoto,* Jun-ichi Kashiwakura,* Toshimitsu Uede,‡ and Tadashi Matsuda* The integrin a9b1 is a key receptor involved in the development of autoimmune diseases.
    [Show full text]
  • Tumour Immunology: NK Cells Bring in the Troops
    RESEARCH HIGHLIGHTS Nature Reviews Immunology | Published online 16 Feb 2018; doi:10.1038/nri.2018.14 Macmillan Publishers Limited TUMOUR IMMUNOLOGY NK cells bring in the troops The presence of conventional type 1 dendritic Xcl1 mRNA. Intracellular flow cytometry analyses cells (cDC1s) in tumours has been associated with of cells from COX-deficient tumours four days enhanced antitumour immunity, but it has been after implantation showed that NK cells expressed higher unclear what promotes their infiltration. A recent CCL5 protein and Xcl1 mRNA, while some rare expression study from Caetano Reis e Sousa and colleagues tumour-infiltrating CD8+ T cells expressed CCL5 now shows that natural killer (NK) cells recruit but not Xcl1. of NK cell cDC1s to the tumour microenvironment by cDC1s express the CCL5 receptors CCR1 and and cDC1 producing the chemokines CCL5 and XCL1. CCR5 as well as XCR1, the receptor for XCL1, signature The same authors previously reported that and the authors showed that they migrate genes in tumours suppress cDC1-dependent CD8+ T cell towards these chemokines in transwell assays. antitumour responses by producing Moreover, antibody-mediated blockade of tumour prostaglandin E2 (PGE2), and that deletion CCL5 and XCL1 in vivo markedly reduced cDC1 samples was of the cyclooxygenase (COX) enzymes that accumulation in COX-deficient tumours. Further associated are necessary for PGE2 synthesis enhances studies revealed that PGE2 reduces NK cell survival antitumour immunity. They therefore compared within tumours and inhibits their production of with increased cDC1 accumulation in the tumours of mice that CCL5 and XCL1, as well as impairing cDC1 patient were implanted with COX-deficient BRAFV600E responsiveness to these chemokines.
    [Show full text]
  • The Role of Specific Chemokines in the Amelioration of Colitis By
    biomolecules Article The Role of Specific Chemokines in the Amelioration of Colitis by Appendicitis and Appendectomy Rajkumar Cheluvappa 1,* ID , Dennis G. Thomas 2 and Selwyn Selvendran 3 ID 1 Department of Medicine, St. George Clinical School, University of New South Wales, Sydney, NSW 2052, Australia 2 Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA; [email protected] 3 Department of Surgery, St. George Hospital, Kogarah, NSW 2217, Australia; [email protected] * Correspondence: [email protected]; Tel.: +61-0406-0406-20; Fax: +61-02-9385-1389 Received: 13 June 2018; Accepted: 16 July 2018; Published: 20 July 2018 Abstract: The appendix contains abundant lymphoid tissue and is constantly exposed to gut flora. When completed at a young age, appendicitis followed by appendectomy (AA) prevents or significantly ameliorates Inflammatory Bowel Diseases (IBDs) in later life. Inflammatory bowel disease comprises Crohn’s disease and ulcerative colitis. Our murine AA model is the only existing experimental model of AA. In our unique model, AA performed in the most proximal colon limits colitis pathology in the most distal colon by curbing T-helper 17 cell activity, diminishing autophagy, modulating interferon activity-associated molecules, and suppressing endothelin vaso-activity-mediated immunopathology. In the research presented in this paper, we have examined the role of chemokines in colitis pathology with our murine AA model. Chemokines are a family of small cytokines with four conserved cysteine residues. Chemokines induce chemotaxis in adjacent cells with corresponding receptors. All 40 known chemokine genes and 24 chemokine receptor genes were examined for gene expression levels in distal colons three days post-AA and 28 days post-AA.
    [Show full text]
  • Products for Chemokine Research
    RnDSy-lu-2945 Products for Chemokine Research The Chemokine Superfamily Chemokines are small cell surface-localized or secreted chemotactic cytokines that bind to and activate specific G protein-coupled chemokine receptors. Most chemokines have at least four conserved N-terminal cysteine residues that form two intramolecular disulfide bonds. Four chemokine subfamilies (CXC, CC, C and CX3C) have been defined based upon the placement of the first two cysteine residues. The CXC chemokine subfamily is characterized by two cysteine residues separated by one amino acid. Within this subfamily, two CXC classes are further defined by the presence or absence of an ELR motif sequence. ELR– CXC chemokines act as chemoattractants for lymphocytes, while ELR+ CXC chemokines are chemoattractants for neutrophils. Additionally, CXC chemokines can mediate angiogenesis.1 The CC chemokine subfamily is defined by two adjacent cysteine CCR1 H: CCL3-5, 7, 8, 13-16, 23, CCL3L1, CCL3L3, CCL4L1, CCL4L2 M: CCL3-7, 9/10 residues. CC chemokines induce inflammatory H: XCL1, 2 XCR1 responses via regulation of monocyte, M: XCL1 macrophage, mast cell, and T cell migration.2 H: CCL2, 7, 8, 13, 16 CCR2 (A or B) M: CCL2, 7, 12 C chemokines are characterized by a single H: CCL26 CX3CR1 cysteine residue and are constitutively expressed H: CX3CL1 in the thymus where they regulate T cell H: CCL5, 7, 8, 11, 13, 14, 15, 24, 26, 28, CCL3L1, CCL3L3 M: CX3CL1 CCR3 M: CCL5, 7, 9/10, 11, 24 differentiation.3 The CX3C chemokine subfamily is defined by two cysteine residues separated by H: CXCL6-8 CXCR1 three amino acids.
    [Show full text]
  • Allergic Asthma T Cells in Human
    XCL1 Enhances Regulatory Activities of CD4 +CD25highCD127low/− T Cells in Human Allergic Asthma This information is current as Khoa D. Nguyen, Alison Fohner, Jerome D. Booker, Chen of September 25, 2021. Dong, Alan M. Krensky and Kari C. Nadeau J Immunol 2008; 181:5386-5395; ; doi: 10.4049/jimmunol.181.8.5386 http://www.jimmunol.org/content/181/8/5386 Downloaded from References This article cites 34 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/181/8/5386.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 25, 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 XCL1 Enhances Regulatory Activities of CD4؉CD25highCD127low/؊ T Cells in Human Allergic Asthma1 Khoa D. Nguyen,* Alison Fohner,* Jerome D. Booker,* Chen Dong,* Alan M. Krensky,† and Kari C. Nadeau2* Chemokine-mediated recruitment of regulatory cell subsets to the airway during inflammation and enhancement of their activities are potential strategies for therapeutic development in allergic asthma (AA).
    [Show full text]