DOCSLIB.ORG

Human Regulatory T Cells Kill Tumor Cells Through Granzyme-Dependent Cytotoxicity Upon Retargeting with a Bispecific Antibody

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Human Regulatory T Cells Kill Tumor Cells Through Granzyme-Dependent Cytotoxicity Upon Retargeting with a Bispecific Antibody Published OnlineFirst July 5, 2013; DOI: 10.1158/2326-6066.CIR-13-0049 Cancer Priority Brief Immunology Research Human Regulatory T Cells Kill Tumor Cells through Granzyme-Dependent Cytotoxicity upon Retargeting with a Bispecific Antibody Bryan D. Choi1,2, Patrick C. Gedeon1,3, James E. Herndon II4, Gary E. Archer1, Elizabeth A. Reap1, Luis Sanchez-Perez1, Duane A. Mitchell1,2,5, Darell D. Bigner2,5, and John H. Sampson1,2,5 Abstract A major mechanism by which human regulatory T cells (Treg) have been shown to suppress and kill autologous immune cells is through the granzyme-perforin pathway. However, it is unknown whether Tregs also possess the capacity to kill tumor cells using similar mechanisms. Bispecific antibodies (bscAb) have emerged as a promising class of therapeutics that activate T cells against tumor antigens without the need for classical MHC-restricted T- cell receptor (TCR) recognition. Here, we show that a bscAb targeting the tumor-specific mutation of the EGF þ þ þ receptor, EGFRvIII, redirects human CD4 CD25 FoxP3 Tregs to kill glioblastoma cells. This activity was significantly abrogated by inhibitors of the granzyme-perforin pathway. Notably, analyses of human primary þ glioblastoma also displayed diffused infiltration of granzyme-expressing FoxP3 T cells. Together, these data suggest that despite their known suppressive functions, tumor-infiltrating Tregs possess potent cytotoxic mechanisms that can be co-opted for efficient tumor cell lysis. Cancer Immunol Res; 1(3); 163–7. Ó2013 AACR. Introduction molecules that possess dual specificity for tumor-associated Despite maximal surgical resection, dose-intensive radio- surface antigens and the CD3 complex on T cells, which allows fi therapy and multimodal chemotherapy, glioblastoma remains them to divalently bind and afford potent, speci c target cell uniformly lethal with a median survival of less than 15 months lysis (8). Because CD3 is universally expressed among T cells, (1). Novel therapies are desperately needed to improve the BiTEs have the theoretical capacity to redirect and activate prognosis of this disease and immunologic targeting of tumor- even Tregs that are elevated and present in tumors of patients specific mutations has emerged as a promising approach (2). with cancer. fi A major barrier that has impeded translation of efficacious Among the few known tumor-speci c antigens, perhaps the immunotherapy is the inability to overcome profound immu- most widely characterized is the truncated mutant EGF recep- nosuppression associated with malignant disease (3). Regula- tor variant type III (EGFRvIII). EGFRvIII is a constitutively activated tyrosine kinase that is frequently expressed on the tory T cells (Tregs) in particular are thought to play a central role in tumor escape from immune-mediated rejection. One mech- surface of glioblastoma and other common neoplasms but is anism by which T are known to suppress and even kill completely absent from healthy tissues (9). regs fi autologous immune cells is through the granzyme-perforin In this study, we show that an EGFRvIII-speci c BiTE, fi pathway (4, 5). Despite this well-characterized cytotoxic capac- bscEGFRvIIIxCD3 (7), successfully redirects highly puri ed ity, whether T can co-opt cytotoxic mechanisms to kill Tregs and activates them in the presence of tumors expressing regs fi tumor cells has yet to be evaluated. EGFRvIII. Despite their known suppressive properties, puri ed þ þ dim/À fi T-cell–activating bispecific antibodies (bscAb), particularly CD4 CD25 CD127 T cells ef ciently lysed EGFRvIII- in vitro those of the bispecific T-cell engager (BiTE) subclass, represent expressing glioblastoma upon redirection and activa- a new therapeutic strategy that has the potential to treat even tion with bscEGFRvIIIxCD3. This activity was found to be bulky, invasive disease (6, 7). BiTEs are tandem single-chain dependent on the granzyme-perforin pathway. Immunohisto- chemical (IHC) analysis from human primary GBMs also displayed diffuse infiltration of activated, granzyme-producing þ FoxP3 cells, showing that T with potent effector functions Authors' Affiliations: 1Duke Brain Tumor Immunotherapy Program, Divi- regs sion of Neurosurgery, Department of Surgery, Departments of 2Pathology, may already be present in tumors even under natural 3Biomedical Engineering, and 4Biostatistics and Bioinformatics, and 5The conditions. Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, North Carolina Previous efforts to enhance antitumor immunity via Treg depletion have been limited, in part due to an inability to Corresponding Author: John H. Sampson; Duke Brain Tumor Immuno- fi fi therapy Program, Division of Neurosurgery, Department of Surgery; Duke ef ciently eliminate suppressive cells that in ltrate tumor University Medical Center; Box 3050; Durham, NC 27710. Phone: 919-684- tissue (10). Alternatively, our data suggest that BiTEs can 9043; Fax: 919-419-1741; E-mail: [email protected] activate even suppressive Tregs to lyse tumor cells by redirect- doi: 10.1158/2326-6066.CIR-13-0049 ing their natural granzyme-mediated cytotoxic potential. Ó2013 American Association for Cancer Research. These findings not only highlight a new mechanism by which www.aacrjournals.org 163 Downloaded from cancerimmunolres.aacrjournals.org on September 26, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst July 5, 2013; DOI: 10.1158/2326-6066.CIR-13-0049 Choi et al. BiTEs may circumvent certain aspects of Treg-mediated added to each well of a 96-well round-bottom plate for an suppression, but also have broader implications with regard additional 24 hours and cells were collected by a cell harvester. to the natural functional role of activated, tumor-infiltrating Counts were conducted using a Wallac 1450 Microbeta Trilux Tregs that express granzyme and perforin in the tumor Liquid Scintillation/Luminescence Counter (Perkin-Elmer). microenvironment. Similarly, cytotoxicity assays were conducted by a standard chromium release assay as previously described by us (7). In Materials and Methods brief, target cells were labeled with 51Cr and incubated with Tumor cell lines and reagents EGFRvIII BiTE and effector cells [E:T ratio, 20:1; incubation The human glioma cell line U87MG and its subline time, 18 hours at 37C; (bscEGFRvIIIxCD3), 10 mg/mL] in a U87MG.DEGFR, which expresses EGFRvIII, are described else- total volume of 200 mL. Following incubation, supernatants where and were kind gifts from Dr. Webster Cavenee at Uni- were removed and measured by gamma counter. Where noted, versity of California, San Diego (11). EGFRvIII expression was for inhibition of the granzyme-perforin axis, concanamycin A verified by flow cytometry using the L8A4 antibody (12). These (CMA, 100 nmol/L; Sigma), Granzyme B Inhibitor I (Z-AAD- cell lines were regularly confirmed to be Mycoplasma-free by CMK, 50 mmol/L; Calbiochem), or ethylene glycol tetracetic nucleic acid hybridization assay (GEN-PROBE MTC-NI). Char- acid (EGTA, 4 mmol/L; Calbiochem) was added to each well. acterization, production, and purification of bscEGFRvIIIxCD3 Inhibitor concentrations were chosen based on previously as well as control antibody constructs were conducted as published studies to establish dependence of cell-mediated previously described by us (7). Antibodies to CD4 (RPA-T4), cytotoxicity on perforin-granzyme activity (4, 13, 14). Before CD25 (M-A251), CD69 (L78), CD152 (BNI3), Granzyme A (CB9), use, each inhibitor was found to have insignificant effects on Granzyme B (GB11), and Perforin (dG9) were purchased from the viability of Tregs following 18 hours incubation at 37 Cas BD Biosciences. Anti-FoxP3 antibody (PCH101) and the FoxP3 assessed by LIVE/DEAD Fixable Violet Dead Cell Stain Kit Staining Buffer Set were purchased from eBioscience and (Invitrogen). Blockade of FasL- and TRAIL-mediated apoptosis intracellular staining was conducted according to manufac- was carried out with antibody clones NOK-1 (25 mg/mL; turer's instructions. Antibodies against human FoxP3 (259D, BD Biosciences) and RIK-2 (25 mg/mL; BD Biosciences), BioLegend) and granzyme B (Cat No. ab4059) were used for respectively. IHC staining. Immunohistochemistry Treg isolation and preparation Tissues for IHC analysis were derived from human brain All human samples were obtained at Duke University Med- tumor biopsy material. Paraffin-embedded tissues were fixed, ical Center (Durham, NC) from individuals who had given cut into 5 mm sections, mounted on glass slides and subjected written, informed consent. Human PBMCs were prepared by to primary and secondary staining using the MACH 2 Double density gradient centrifugation from buffy coats of healthy Stain 1 polymer Detection Kit (Biocare Medical) according to donor leukapheresis. Highly purified regulatory T cells were the manufacturer's instructions. Diaminobenzidine (DAB) and þ isolated from PBMCs by magnetic separation using the CD4 AminoEthyl Carbazole (AEC) were used to detect granzyme B þ À CD25 CD127dim/ Regulatory T Cell Isolation Kit II and and FoxP3, respectively. AutoMACS Separator (Miltenyi Biotec) according to the man- ufacturer's instructions. Following isolation, purity was con- Statistical analysis firmed by flow cytometric analysis to be more than 95% Groups were compared using a two-sample two-tailed t test þ þ (CD25 FoxP3 ). Where noted, purified Tregs were prepared and statistical significance was determined at a value of P < 0.05. with the T Expansion Kit (Miltenyi Biotec) at a MACSiBead reg Results
Load more

Recommended publications
  • Regulatory Lymphocytes: the Dice That Resolve the Tumor Endgame Subhadip Pati, Anandi Chowdhury, Sumon Mukherjee, Aharna Guin, Shravanti Mukherjee and Gaurisankar Sa*
    Pati et al. Applied Cancer Research (2020) 40:7 Applied Cancer Research https://doi.org/10.1186/s41241-020-00091-0 REVIEW Open Access Regulatory lymphocytes: the dice that resolve the tumor endgame Subhadip Pati, Anandi Chowdhury, Sumon Mukherjee, Aharna Guin, Shravanti Mukherjee and Gaurisankar Sa* Abstract A large number of cancer patients relapse after chemotherapeutic treatment. The immune system is capable of identifying and destroying cancer cells, so recent studies have highlighted the growing importance of using combinatorial chemotherapy and immunotherapy. However, many patients have innate or acquired resistance to immunotherapies. Long-term follow-up in a pooled meta-analysis exhibited long-term survival in approximately 20% of patients treated with immune checkpoint inhibitors or the adoptive transfer of chimeric T cells. It has been reported that high levels of immunoregulatory cells in cancer patients contribute to immunotherapy resistance via immunosuppression. Among the most important regulatory cell subtypes are the CD4+ T-regulatory cells (Tregs), identified by their expression of the well-characterized, lineage-specific transcription factor FOXP3. In addition to CD4+ Tregs, other regulatory cells present in the tumor microenvironment, namely CD8+ Tregs and IL10-producing B-regulatory cells (Bregs) that also modulate the immune response in solid and lymphoid tumors. These cells together have detrimental effects on tumor immune surveillance and anti-tumor immunity. Therefore, targeting these regulatory lymphocytes will be crucial in improving treatment outcomes for immunotherapy. Keywords: Breg, CTLA4, FOXP3, Immunotherapy, IL10, PDL1, Treg Background neo-antigens, which are not present in non-cancerous The suppression of anti-tumor immune responses and cells [5]. These neo-antigens offer a clinical advantage augmentation of tumor-promoting immune responses since the tumor cells expressing neo-antigens are then both contribute to tumor progression [1].
    [Show full text]
  • Regulatory T Cell Research
    Regulatory T cell research Unique kits for cell isolation Harmonized cell culture and expansion tools Convenient functional assay tools Germany/Austria/ Benelux France Nordics and Baltics South Korea Switzerland Miltenyi Biotec B.V. Miltenyi Biotec SAS Miltenyi Biotec Norden AB Miltenyi Biotec Korea Co., Ltd Reliable flow cytometry analysis Miltenyi Biotec GmbH Schipholweg 68 H 10 rue Mercoeur Scheelevägen 17 Arigi Bldg. 8F Friedrich-Ebert-Straße 68 2316 XE Leiden 75011 Paris, France 223 70 Lund 562 Nonhyeon-ro 51429 Bergisch Gladbach The Netherlands Phone +33 1 56 98 16 16 Sweden Gangnam-gu Germany [email protected] Fax +33 1 56 98 16 17 [email protected] Seoul 06136, South Korea Phone +49 2204 8306-0 Customer service [email protected] Customer service Sweden Phone +82 2 555 1988 Fax +49 2204 85197 The Netherlands Phone 0200-111 800 Fax +82 2 555 8890 [email protected] Phone 0800 4020120 Italy Fax 046-280 72 99 [email protected] Fax 0800 4020100 Miltenyi Biotec S.r.l. Customer service Denmark USA/Canada Customer service Belgium Via Persicetana, 2/D Phone 80 20 30 10 Spain Miltenyi Biotec Inc. Phone 0800 94016 40012 Calderara di Reno (BO) Fax +46 46 280 72 99 Miltenyi Biotec S.L. 2303 Lindbergh Street Fax 0800 99626 Italy Customer service C/Luis Buñuel 2 Auburn, CA 95602, USA Customer service Luxembourg Phone +39 051 6 460 411 Norway, Finland, Iceland, Ciudad de la Imagen Phone 800 FOR MACS Phone 800 24971 Fax +39 051 6 460 499 and Baltic countries 28223 Pozuelo de Alarcón (Madrid) Phone +1 530 888 8871 Fax 800 24984 [email protected] Phone +46 46 280 72 80 Spain Fax +1 877 591 1060 Fax +46 46 280 72 99 Phone +34 91 512 12 90 [email protected] China Japan Fax +34 91 512 12 91 Miltenyi Biotec Technology & Miltenyi Biotec K.K.
    [Show full text]
  • CD8+CD122+Cd49dlow Regulatory T Cells Maintain T-Cell
    + + CD8 CD122 CD49dlow regulatory T cells maintain T-cell homeostasis by killing activated T cells via Fas/FasL-mediated cytotoxicity Kazuyuki Akanea,b, Seiji Kojimab, Tak W. Makc,1, Hiroshi Shikud,e, and Haruhiko Suzukia,1 aDepartment of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan; bDepartment of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan; cCampbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario, Canada M5G 2M9; dDepartment of Cancer Vaccine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan; and eDepartment of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan Contributed by Tak W. Mak, January 15, 2016 (sent for review October 5, 2015; reviewed by Toshiaki Ohteki and Heiichiro Udono) The Fas/FasL (CD95/CD178) system is required for immune regula- regulatory action are available. Therefore, it is not clear precisely tion; however, it is unclear in which cells, when, and where Fas/FasL which subset of T cells express FasL or where Fas/FasL-dependent + molecules act in the immune system. We found that CD8+CD122+ CD8 Tregs, if such cells exist, are located and at which point cells, which are mostly composed of memory T cells in compari- they function. Thus, the ultimate pathophysiological role of the + − son with naïve cells in the CD8 CD122 population, were previ- Fas/FasL system is still unknown. ously shown to include cells with regulatory activity and could Regulation of the immune reaction is of pivotal importance be separated into CD49dlow cells and CD49dhigh cells.
    [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]
  • 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]
  • Regulatory T-Cell Therapy in Crohn's Disease: Challenges and Advances
    Recent advances in basic science Regulatory T- cell therapy in Crohn’s disease: Gut: first published as 10.1136/gutjnl-2019-319850 on 24 January 2020. Downloaded from challenges and advances Jennie N Clough ,1,2 Omer S Omer,1,3 Scott Tasker ,4 Graham M Lord,1,5 Peter M Irving 1,3 1School of Immunology and ABStract pathological process increasingly recognised as Microbial Sciences, King’s The prevalence of IBD is rising in the Western world. driving intestinal inflammation and autoimmunity College London, London, UK 2NIHR Biomedical Research Despite an increasing repertoire of therapeutic targets, a is the loss of immune homeostasis secondary to Centre at Guy’s and Saint significant proportion of patients suffer chronic morbidity. qualitative or quantitative defects in the regulatory Thomas’ NHS Foundation Trust Studies in mice and humans have highlighted the critical T- cell (Treg) pool. and King’s College, London, UK + 3 role of regulatory T cells in immune homeostasis, with Tregs are CD4 T cells that characteristically Department of defects in number and suppressive function of regulatory Gastroenterology, Guy’s and express the high- affinity IL-2 receptor α-chain Saint Thomas’ Hospitals NHS T cells seen in patients with Crohn’s disease. We review (CD25) and master transcription factor Forkhead Trust, London, UK the function of regulatory T cells and the pathways by box P-3 (Foxp3) which is essential for their suppres- 4 Division of Transplantation which they exert immune tolerance in the intestinal sive phenotype and stability.4–6
    [Show full text]
  • Regulatory T Cells Suppress Th17 Cell Ca2+ Signaling in the Spinal Cord During Murine Autoimmune Neuroinflammation
    + Regulatory T cells suppress Th17 cell Ca2 signaling in the spinal cord during murine autoimmune neuroinflammation Shivashankar Othya,1,2, Amit Jairamana,1, Joseph L. Dynesa, Tobias X. Donga, Cornelia Tunea,3, Andriy V. Yeromina, Angel Zavalaa, Chijioke Akunwafoa, Fangyi Chena, Ian Parkera,b, and Michael D. Cahalana,c,2 aDepartment of Physiology & Biophysics, University of California, Irvine, CA 92697; bDepartment of Neurobiology & Behavior, University of California, Irvine, CA 92697; and cInstitute for Immunology, University of California, Irvine, CA 92697 Contributed by Michael D. Cahalan, June 11, 2020 (sent for review April 15, 2020; reviewed by Jason G. Cyster and Stefan Feske) T lymphocyte motility and interaction dynamics with other with several autoimmune and systemic inflammatory diseases, and immune cells are vital determinants of immune responses. Regu- are considered to be the main pathogenic cells in the experimental latory T (Treg) cells prevent autoimmune disorders by suppressing autoimmune encephalomyelitis (EAE) murine model of multiple excessive lymphocyte activity, but how interstitial motility pat- sclerosis (6, 7). However, no studies have yet tracked associations terns of Treg cells limit neuroinflammation is not well understood. between endogenous Th17 and Treg cells in relation to APCs We used two-photon microscopy to elucidate the spatial organi- within the complex inflammatory tissue environment. zation, motility characteristics, and interactions of endogenous A well-established signal transduction pathway links TCR binding Treg and Th17 cells together with antigen-presenting cells (APCs) of peptide-MHC on APCs to proximal signaling events leading to within the spinal cord leptomeninges in experimental autoim- 2+ generation of IP3 and consequent depletion of Ca from the en- mune encephalomyelitis (EAE), an animal model of multiple doplasmic reticulum (ER), mobilization of ER STIM1 proteins to sclerosis.
    [Show full text]
  • Regulatory T Cells Suppress Inflammation and Blistering in Pemphigoid Diseases
    ORIGINAL RESEARCH published: 24 November 2017 doi: 10.3389/fimmu.2017.01628 Regulatory T Cells Suppress inflammation and Blistering in Pemphigoid Diseases Katja Bieber1*‡, Shijie Sun1†‡, Mareike Witte2, Anika Kasprick1, Foteini Beltsiou1, Martina Behnen3, Tamás Laskay3, Franziska S. Schulze1, Elena Pipi1, Niklas Reichhelm1, René Pagel4, Detlef Zillikens 2, Enno Schmidt1,2, Tim Sparwasser 5, Kathrin Kalies4 and Ralf J. Ludwig1,2 1 Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany, 2 Department of Dermatology, University of Lübeck, Lübeck, Germany, 3 Department for Infectious Diseases and Microbiology, University of Lübeck, Edited by: Lübeck, Germany, 4 Institute of Anatomy, University of Lübeck, Lübeck, Germany, 5 Institute for Experimental Infection Kjetil Taskén, Research, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between the Helmholtz University of Oslo, Norway Centre for Infection Research and the Hannover Medical School, Hanover, Germany Reviewed by: Zlatko Kopecki, University of South Australia, Regulatory T cells (Tregs) are well known for their modulatory functions in adaptive Australia immunity. Through regulation of T cell functions, Tregs have also been demonstrated Hajo Haase, to indirectly curb myeloid cell-driven inflammation. However, direct effects of Tregs Technische Universität Berlin, Germany on myeloid cell functions are insufficiently characterized, especially in the context of Johan Van Der Vlag, myeloid cell-mediated diseases, such as pemphigoid diseases (PDs). PDs are caused Radboud University Nijmegen, Netherlands by autoantibodies targeting structural proteins of the skin. Autoantibody binding triggers *Correspondence: myeloid cell activation through specific activation of Fc gamma receptors, leading to skin Katja Bieber inflammation and subepidermal blistering. Here, we used mouse models to address the [email protected] potential contribution of Tregs to PD pathogenesis in vivo.
    [Show full text]
  • Regulatory T Cells Inhibit T Cell Activity by Downregulating CD137 Ligand Via CD137 Trogocytosis
    cells Article Regulatory T Cells Inhibit T Cell Activity by Downregulating CD137 Ligand via CD137 Trogocytosis Khang Luu 1,2,3,4,5 , Mugdha Vijay Patwardhan 1,2,3 , Qun Zeng 1,2,3, Stina L. Wickström 5 , Andreas Lundqvist 5 and Herbert Schwarz 1,2,3,4,* 1 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore; [email protected] (K.L.); [email protected] (M.V.P.); [email protected] (Q.Z.) 2 NUS Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore 3 NUSMED Immunology Translational Research Programme, National University of Singapore, Singapore 117456, Singapore 4 Integrative Sciences and Engineering Programme, National University of Singapore, Singapore 117456, Singapore 5 Department of Oncology-Pathology, Karolinska Institutet, 171 64 Stockholm, Sweden; [email protected] (S.L.W.); [email protected] (A.L.) * Correspondence: [email protected] Abstract: CD137 is a costimulatory molecule expressed on activated T cells. CD137 ligand (CD137L) is expressed by antigen presenting cells (APC), which use the CD137—CD137L system to enhance immune responses. It was, therefore, surprising to discover CD137 expression on regulatory T cells (Treg). The function of CD137 in Treg are controversial. While some studies report that CD137 signalling converts Treg to effector T cells (Teff), other studies find that CD137-expressing Treg display a stronger inhibitory activity than CD137- Treg. Here, we describe that CD137 on Treg binds Citation: Luu, K.; Patwardhan, M.V.; Zeng, Q.; Wickström, S.L.; Lundqvist, A.; to CD137L on APC, upon which one of the two molecules is transferred via trogocytosis to the other Schwarz, H.
    [Show full text]
  • Cellular Immunology 339 (2019) 29–32
    Cellular Immunology 339 (2019) 29–32 Contents lists available at ScienceDirect Cellular Immunology journal homepage: www.elsevier.com/locate/ycimm Novel regulatory Th17 cells and regulatory B cells in modulating autoimmune diseases T ⁎ Bhagirath Singha,b,c, , Kelly L. Summersa,b,d, Steven M. Kerfoota,b a Centre for Human Immunology, University of Western Ontario, London, ON, Canada b Department of Microbiology and Immunology, University of Western Ontario, London, ON, Canada c Robarts Research Institute, University of Western Ontario, London, ON, Canada d Lawson Health Research Institute, London, ON, Canada ARTICLE INFO ABSTRACT Keywords: Pathogenic lymphocytes aberrantly recognize and mount an immune response against self-antigens, leading to Autoimmune diseases the destruction of healthy cells, tissues and organs. Recent studies have shown that both B and T lymphocytes Breg cells contribute to the development, prevention and modulation of various autoimmune diseases. Regulatory T and B Regulatory Th17 cells cell subsets appear to play a prominent role in the prevention of autoimmune diseases. The recent identification Treg17 cells of novel regulatory Th17 cells, termed as Treg17 cells, has expanded the scope of regulatory T lymphocytes (Treg cells) in the prevention of autoimmune diseases. Similarly, novel regulatory B cell subsets, termed as Breg cells, acting on their own or by inducing Treg cells have extended the role of B lymphocytes in the prevention and regulation of autoimmune diseases. We suggest that Treg17 cells and Breg cells have an important im- munoregulatory role in autoimmune diseases. 1. Introduction 1.1. Regulatory cells and autoimmunity Autoimmune diseases generally result from the breakdown of the The crucial role of regulatory cells in self-tolerance and auto- immunoregulatory mechanisms that control autoreactive T and/or B immunity has been established in many autoimmune diseases.
    [Show full text]
  • Regulatory T Cells Fail to Suppress Fast Homeostatic Proliferation in Vitro
    life Article Regulatory T Cells Fail to Suppress Fast Homeostatic Proliferation In Vitro Daniil Shevyrev 1,*, Valeriy Tereshchenko 2, Elena Blinova 1, Nadezda Knauer 1, Ekaterina Pashkina 1, Alexey Sizikov 3 and Vladimir Kozlov 1 1 Laboratory of Clinical Immunopathology, Research Institute for Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; [email protected] (E.B.); [email protected] (N.K.); [email protected] (E.P.); [email protected] (V.K.) 2 Laboratory of Molecular Immunology, Research Institute for Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; [email protected] 3 Rheumatology Department, Research Institute for Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; [email protected] * Correspondence: [email protected]; Tel.: +7-923-134-5505 Abstract: Homeostatic proliferation (HP) is a physiological process that reconstitutes the T cell pool after lymphopenia involving Interleukin-7 and 15 (IL-7 and IL-15), which are the key cytokines regulating the process. However, there is no evidence that these cytokines influence the function of regulatory T cells (Tregs). Since lymphopenia often accompanies autoimmune diseases, we decided to study the functional activity of Tregs stimulated by HP cytokines from patients with rheumatoid arthritis as compared with that of those from healthy donors. Since T cell receptor (TCR) signal strength determines the intensity of HP, we imitated slow HP using IL-7 or IL-15 and fast HP using a combination of IL-7 or IL-15 with anti-CD3 antibodies, cultivating Treg cells with peripheral blood mononuclear cells (PBMCs) at a 1:1 ratio. We used peripheral blood from 14 patients with rheumatoid Citation: Shevyrev, D.; Tereshchenko, arthritis and 18 healthy volunteers.
    [Show full text]
  • Role of Regulatory T Cells in Rheumatoid Arthritis: Facts and Hypothesis
    Autoimmun Highlights (2010) 1:45–51 DOI 10.1007/s13317-010-0008-2 REVIEW ARTICLE Role of regulatory T cells in rheumatoid arthritis: facts and hypothesis Alessia Alunno • Elena Bartoloni • Giuseppe Nocentini • Onelia Bistoni • Simona Ronchetti • Maria Grazia Petrillo • Carlo Riccardi • Roberto Gerli Received: 01 April 2010 / Accepted: 06 April 2010 / Published online: … … … © Springer-Verlag 2010 Abstract Regulatory T cells (Treg) are a CD4+ lympho- Introduction cyte subset involved in self-tolerance and autoimmunity prevention. There is evidence for a phenotypic and/or Regulatory T (Treg) cells are a specialized CD4+ lym- functional impairment of this cell subset during the natu- phocyte subset able to modulate immune response to ral history of several chronic autoimmune/inflammatory environmental pathogens as well as to prevent immune diseases, including rheumatoid arthritis (RA). Although responses against inappropriate targets, including self the intracellular transcription factor FoxP3 is thought to antigens [1]. In fact, Treg cells can suppress autoreactive be the master regulator of Treg cell function, a number of lymphocyte clones that have escaped the negative selec- other molecules expressed on the cell surface have been tion in the thymus by different mechanisms, thus prevent- proposed for the identification of Treg cells. This is ing the activation and expansion of these effector cell important in order to favour their possible selective isola- subsets. Suppression can be either in a cell–cell contact tion and in the development of new therapeutic strategies. manner or via soluble factors produced by Treg cells In the present paper, available data on phenotypic and themselves [2, 3]. functional characterization of Treg cells in both peripher- The well-known role played by T cells in the develop- al blood and synovial fluid from RA patients are reviewed ment of autoimmunity was characterized in the mid- and their possible pathogenic role in triggering and per- 1990s by Sakaguchi et al.
    [Show full text]