CD27 CD70 Is Downregulated by Interaction With

Total Page:16

File Type:pdf, Size:1020Kb

CD27 CD70 Is Downregulated by Interaction With CD70 Is Downregulated by Interaction with CD27 Mirela Kuka, Ivana Munitic, Maria Letizia Giardino Torchia and Jonathan D. Ashwell This information is current as of September 25, 2021. J Immunol 2013; 191:2282-2289; Prepublished online 2 August 2013; doi: 10.4049/jimmunol.1300868 http://www.jimmunol.org/content/191/5/2282 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2013/08/06/jimmunol.130086 Material 8.DC1 References This article cites 35 articles, 19 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/191/5/2282.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 September 25, 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 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology CD70 Is Downregulated by Interaction with CD27 Mirela Kuka,1,2 Ivana Munitic,1,3 Maria Letizia Giardino Torchia, and Jonathan D. Ashwell Engagement of the receptor CD27 by CD70 affects the magnitude and quality of T cell responses in a variety of infection models, and exaggerated signaling via this pathway results in enhanced immune responses and autoimmunity. One means by which signaling is regulated is tight control of cell surface CD70, which is expressed on dendritic cells (DCs), T cells, and B cells only upon activation. In this article, we show that a second level of regulation also is present. First, although undetectable on the cell surface by flow cytom- etry, immature DCs have a small pool of CD70 that continuously recycles from the plasma membrane. In addition, surface levels of CD70 on DCs and T cells were higher in mice deficient in CD27, or on DCs for which the interaction between CD70 and CD27 was precluded by blocking Abs. Binding of CD70 by its receptor resulted in downregulation of CD70 transcription and protein levels, suggesting that CD70-mediated “reverse signals” regulate its own levels. Therefore, the ability of CD70 to trigger costimulation is self-regulated when it binds its complementary receptor. The Journal of Immunology, 2013, 191: 2282–2289. Downloaded from nteraction between the costimulatory receptor CD27 and its restricted, and is barely detectable on the cell surface at steady state, ligand CD70 is required for optimal T cell activation (1–3). and even then only rare cells in the thymic medulla and the lamina I Studies using CD27- and CD70-deficient mice or anti-CD70 propria are CD70+ (17–20). Transient transcriptional upregulation of blocking Abs have found defects in primary and/or secondary T cell CD70 occurs in dendritic cells (DCs) activated via TLR- or CD40- responses in a variety of infectious models (4–8). Furthermore, mediated stimulation and in Ag-activated T and B cells (6, 20). In manipulations that increase CD27–CD70 interactions have been DCs, where its expression seems to be most relevant, CD70 is http://www.jimmunol.org/ successfully used in experimental vaccination protocols (9, 10). It is transported by the invariant chain to late endocytic structures, where notable that a fine line exists between beneficial and deleterious it colocalizes with MHC-II molecules (21, 22). Upon interaction of CD70-mediated effects. For example, whereas efficient clearance activated DCs with cognate CD4 T cells, CD70 is codelivered to the of acute lymphocytic choriomeningitis virus (LCMV) strains requires immune synapse with MHC-II, ensuring optimal T cell stimulation. CD27 occupancy by CD70, this interaction precludes clearance of Uncontrolled CD27–CD70 interactions have detrimental effects. the chronic LCMV strain (7, 8, 11). Therefore, the existence of In mouse models where CD70 was constitutively expressed on regulatory mechanisms for the CD70–CD27 pathway ensures ef- B cells, DCs, or T cells, a continuous generation of effector T cells fective and prevents deleterious immune responses. was observed, which in B cell and DC CD70 transgenics resulted Normally, tight control of CD27 and CD70 expression avoids in an autoimmune disease and death (23–25). In contrast, consti- by guest on September 25, 2021 excessive T cell activation. CD27, a member of the TNFR family, is tutive CD70 expression on DCs was sufficient to break peripheral constitutively expressed by T cells as a membrane-bound homodimer, tolerance and, among other things, generate tumor-specific respon- and its surface levels change during T cell activation (3). The baseline ses to peptide immunization without the need for adjuvants (24). In level in resting naive and memory T cells is upregulated during the addition to these observations made in transgenic mice, the im- first days after TCR engagement because of increased transcription portance of excessive CD27–CD70 interactions has been demon- (12–14). Notably, surface levels of CD27 are downregulated during strated in a chronic LCMV infection model (11). Continuous CD27 T cell effector differentiation by shedding and/or decreased tran- engagement, likely mediated by a subset of CD70-expressing scription, and some terminally differentiated effector memory T cells B cells, led to T cell cytokine-mediated splenic germinal center and (TEM) retain a CD27-negative phenotype (13–15). CD27 can also be marginal zone destruction, thus precluding the generation of a neu- reversibly downregulated on memory CD8 T cells that enter non- tralizing Ab response. lymphoid organs (16). In contrast, expression of CD70, a homotri- It is generally believed that the downregulation of T cell CD27 meric transmembrane member of the TNF family, is much more levels during persistent stimulation is an activation-intrinsic event. However, some evidence suggests that it is also the interaction with Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of CD70 that results in decreased CD27levelsintheabsenceofacti- Health, Bethesda, MD 20892 vation. For example, T cell coculture with B cell lines expressing CD70 1M.K. and I.M. contributed equally to this work. triggered CD27 downregulation, and even naive T cells in CD70 Tg 2Current address: Division of Immunology, Transplantation and Infectious Diseases, mice had substantially lower CD27 levels (26, 27). In the course of San Raffaele Scientific Institute, Milan, Italy. studying mice deficient in either CD27 or CD70, we made the un- 3Current address: Department of Biotechnology, University of Rijeka, Rijeka, Croatia. expected observation that in the absence of one the other was up- Received for publication March 29, 2013. Accepted for publication June 26, 2013. regulated. In this article, we show by Ab blocking and genetic This work was supported by the Intramural Research Program of the Center for manipulation that the relationship between CD27 and CD70 expres- Cancer Research, National Cancer Institute, National Institutes of Health. sion is reciprocal and mediated by direct protein–protein interactions. Address correspondence and reprint requests to Dr. Jonathan D. Ashwell, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Building 37, Room 3002C, Bethesda, MD 20892. E-mail address: [email protected] Materials and Methods Mice The online version of this article contains supplemental material. Abbreviations used in this article: CHX, cycloheximide; LCMV, lymphocytic cho- C57BL/6 (B6) mice were obtained from Frederick Cancer Research Facility 2/2 riomeningitis virus; DMFI, change in mean fluorescence intensity; poly(I:C), poly- (Frederick, MD). CD70 mice backcrossed to B6 for 13 generations 2 2 inosinic-polycytidylic acid; WT, wild-type. were described (8). CD27 / mice (4) were a gift from Jannie Borst www.jimmunol.org/cgi/doi/10.4049/jimmunol.1300868 The Journal of Immunology 2283 (The Netherlands Cancer Institute, Amsterdam, The Netherlands) and were CD272/2, and CD702/2 mice were infected i.p. with 2 3 105 PFU maintained in our facility. The National Cancer institute Animal Care and LCMV. Use Committee approved all animal studies. Cell stimulation and flow cytometry Reagents Splenocytes were cultured at a concentration of 5 3 106 cells per milliliter Abs to CD27, TCR-b, B220, CD16/CD32 clone 2.4G2 (Fc block), iso- and stimulated with poly(I:C) (30 mg/ml) for 22 h or primed with IFN-g type controls, and fixation and permeabilization buffers were obtained (50 ng/ml) for 2 h and then stimulated with LPS (200 ng/ml) for an ad- from BD Biosciences. The unconjugated Ab to CD70 (clone FR70), the ditional 20 h. In some experiments, cells were treated for 15 min with fluorochrome-conjugated Abs to CD70 (clone FR70), CD11c and MHC anti-CD27 blocking Ab (5 mg/ml) or with isotype control prior to stim- class II, the blocking Ab to CD27 (clone LG.3A10), the isotype control, ulation. In internalization experiments, anti-CD70 PE-conjugated Ab was and recombinant IFN-g were purchased from eBioscience. LCMVArmstrong added to the cultures after stimulation at the indicated time points, at a 53b (LCMV) was a gift from Rafi Ahmed (Emory University School of concentration of 2 mg/ml. Cells were treated or not with CHX (20 mg/ml) b Medicine, Atlanta, GA). GP33-41 H-2D (GP33) tetramers were obtained 1 h before adding anti-CD70 PE-conjugated Ab. For staining of surface from the National Institutes of Health Tetramer Core Facility at Emory molecules, CD16/CD32 clone 2.4G2 was added to block Fc-receptor University. Power SYBR Green was obtained from Applied Biosystems.
Recommended publications
  • 7432.Full.Pdf
    CD27 Is Acquired by Primed B Cells at the Centroblast Stage and Promotes Germinal Center Formation This information is current as Yanling Xiao, Jenny Hendriks, Petra Langerak, Heinz Jacobs of September 29, 2021. and Jannie Borst J Immunol 2004; 172:7432-7441; ; doi: 10.4049/jimmunol.172.12.7432 http://www.jimmunol.org/content/172/12/7432 Downloaded from References This article cites 43 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/172/12/7432.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 29, 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 © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology CD27 Is Acquired by Primed B Cells at the Centroblast Stage and Promotes Germinal Center Formation1 Yanling Xiao, Jenny Hendriks, Petra Langerak, Heinz Jacobs, and Jannie Borst2 Studies on human B cells have featured CD27 as a marker and mediator of the B cell response.
    [Show full text]
  • Uva-DARE (Digital Academic Repository)
    UvA-DARE (Digital Academic Repository) Contributions of CD27 and relatives to the specific immune response Hendriks, J.A. Publication date 2004 Link to publication Citation for published version (APA): Hendriks, J. A. (2004). Contributions of CD27 and relatives to the specific immune response. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:24 Sep 2021 Chapter 5 CD27 is acquired by primed B cells at the centroblast stage and promotes germinal center formation. Yanling Xiao, Jenny Hendriks, Petra Langerak, Heinz Jacobs and Jannie Borst The Journal of Immunology 2004 172: 7432-7441 67 68 CD27 Is Acquired by Primed B Cells at the Centroblast Stage and Promotes Germinal Center Formation1 Yanling Xiao, Jenny Hendriks, Petra Langerak, Heinz Jacobs, and Jannie Borst2 Studies on human B cells have featured CD27 as a marker and mediator of the B cell response.
    [Show full text]
  • Uva-DARE (Digital Academic Repository)
    UvA-DARE (Digital Academic Repository) Molecular basis of CD4+ T cell help for the cytotoxic T cell response Ahrends, T.J. Publication date 2018 Document Version Other version License Other Link to publication Citation for published version (APA): Ahrends, T. J. (2018). Molecular basis of CD4+ T cell help for the cytotoxic T cell response. General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl) Download date:08 Oct 2021 CURRICULUM VITAE LIST OF PUBLICATIONS & WORD OF THANKS ADDENDUM CURRICULUM VITAE Tomasz Ahrends was born on December 30th, 1988 in Gdańsk (Poland). In 2010 he obtained Bachelor’s degree in Biotechnology at the Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk. Subsequently, he continued his education with a Master’s degree in Biotechnology, which he fnished in 2012.
    [Show full text]
  • PDF Hosted at the Radboud Repository of the Radboud University Nijmegen
    PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/27226 Please be advised that this information was generated on 2021-09-26 and may be subject to change. 1142 G. D. Keizer, J. Borst, C. G. Figdor et al Eur. J. Immunol. 1985.15: 1142-1147 Gerrit D. Keizer0, Jannie Borst°, Biochemical and functional characteristics of the Carl G. Figdor0 , Hergen Spits0 , Frank MiedemaA, Cox TerhorstD human leukocyte membrane antigen family LFA-1, and Jan E. De Vries0 Mo-1 and pl50,95* Division of Immunology, The Netherlands Cancer Institute (Antoni The human leukocyte function-associated (LFA-1) antigen, the monocyte differentia­ van Leeuwenhoek Huis)0 , Amsterdam, tion antigen Mo-1 which is characterized as the C3bi receptor and the glycoprotein Central Laboratory of the Netherlands p i50,95 are characterized biochemically. Immunoprecipitations carried out with 6 Red Cross Blood Transfusion ServiceA, different monoclonal antibodies (mAb) against LFA-1 indicated that four mAb (SPV- Amsterdam and Dana-Farber Cancer Ll, SPV-L5, SPV-L7 and SPV-L11) were directed against the a chain, whereas mAb Institute0, Boston CLB54 and MHM-23 were found to react with the common |3 chain of LFA-1, Mo-1 and p 150,95. LFA-1 and Mo-1 expressed on KG-1 cells or lymphocytes, monocytes and granulocytes from one donor were homogeneous. Interestingly the a chain of pl50,95 showed heterogeneity. The molecular weight of the a chain expressed on monocytes was consistently higher than that of the a chain on granulocytes.
    [Show full text]
  • Radio-Immunotherapy in Cancer
    Radio-immunotherapy in cancer Inge Verbrugge The Netherlands Cancer Institute Radiotherapy • One of three /four main treatment modalities • Used in ~50% of cancer patients • Administered locally: minimizes normal tissue damage Effects of radiotherapy on tumor cell clonogenicity DNA damage 1. (Irreversible) cell cycle arrest senescence 2. Death due to mitotic catastrophe 3. Apoptotic cell death Radiotherapy alone may not be curative RADIOTHERAPY Curing metastasized cancer with systemic therapy • Immunotherapy - Eliciting systemic anti-tumor cytotoxic T cell (CTL) responses (CTL) MHC I Radiotherapy: Clinical systemic (=‘abscopal’) responses Pre-radiotherapy Post-radiotherapy ‘Abscopal Effect’ Ohba K et al., Gut 1998;43:575-577 Radiotherapy may support local and systemic tumor immunity Radiotherapy may support local and systemic tumor immunity Co-stimulation ‘abscopal effect’ Established tumors evade immune responses Bottlenecks 1. Lack of recognizable ‘tumor’ antigens 2. Lack of ‘danger signals’ 3. Lack of T cell infiltration into tumor 4. Inhibition CTL activity by tumor / tumor micro-environment Antibodies modulating T cell responses Ipilimumab Pembrolizumab Nivolumab Mellman I et al., Nature 2011;480:480-489 Antibodies modulating T cell responses Ipilimumab Pembrolizumab Nivolumab Mellman I et al., Nature 2011;480:480-489 Antibody-based immunotherapy: local and systemic effects Co-inhibitory receptor Co-stimulatory receptor Radio-immunotherapy: Combining radiotherapy with immunotherapy Blocking coinhibition α-PD-1, α-CD137 Costimulation Radio-immunotherapy promise: Achieving SYSTEMIC synergism by combining LOCAL radiotherapy with immune-modulation Radio-immunotherapy: opportunities Blocking coinhibition α-PD-1, α-CD137 Costimulation 1. Inducing curative local combined responses 2. Achieving systemic combined effect by promoting relevant immune responses Radio-immunotherapy induces local tumor control α-PD-1 α-PD-1, α-CD137 α-CD137 Achieving systemic combined effects by radio-immunotherapy Blocking coinhibition α-PD-1, α-CD137 Costimulation 2.
    [Show full text]
  • Effector T Cell Pool + CD8 Costimulation to Promote
    CD8+ T Cells Produce the Chemokine CXCL10 in Response to CD27/CD70 Costimulation To Promote Generation of the CD8 + Effector T Cell Pool This information is current as of October 2, 2021. Victor Peperzak, Elise A. M. Veraar, Yanling Xiao, Nikolina Babala, Klaske Thiadens, Marieke Brugmans and Jannie Borst J Immunol 2013; 191:3025-3036; Prepublished online 12 August 2013; Downloaded from doi: 10.4049/jimmunol.1202222 http://www.jimmunol.org/content/191/6/3025 Supplementary http://www.jimmunol.org/content/suppl/2013/08/12/jimmunol.120222 http://www.jimmunol.org/ Material 2.DC1 References This article cites 56 articles, 29 of which you can access for free at: http://www.jimmunol.org/content/191/6/3025.full#ref-list-1 Why The JI? Submit online. by guest on October 2, 2021 • 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 © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology CD8+ T Cells Produce the Chemokine CXCL10 in Response to CD27/CD70 Costimulation To Promote Generation of the CD8+ Effector T Cell Pool Victor Peperzak,1 Elise A.
    [Show full text]
  • Pulling the Strings on Anti-Cancer Immunity Issue Date: 2017-02-07
    Cover Page The handle http://hdl.handle.net/1887/45885 holds various files of this Leiden University dissertation. Author: Kersten, K. Title: Pulling the strings on anti-cancer immunity Issue Date: 2017-02-07 Pulling the strings on anti-cancer immunity Kelly Kersten About the cover: Based on the research described in this thesis and inspired by the song ‘Master of Puppets’ by Metallica, I envision cancer as a puppet-master restraining the protective function of the immune system. Part of my PhD work has focused on how tumor cells manipulate the function of immune cells to favor their spread throughout the body. In other words, cancer is pulling the strings on anti-cancer immunity to prevent destruction by the immune system. With the recent advances of combinatorial anti-cancer therapies (including immunomodulatory drugs) we can gain back control over the strings on anti-cancer immunity. Cover design: Kelly Kersten & Tomasz Ahrends Artwork: Tomasz Ahrends Lay-out: Jasper Koning ([email protected]) Printing: Gildeprint, Enschede ISBN: 978-94-6233-496-0 The printing of the thesis was financially supported by the NKI-AVL. ©2016 by Kelly Kersten. All rights reserved. No part of this thesis may be reproduced, stored in a retrieval system, or transmitted in any form or by any means without prior permission of the author and the publisher holding the copyright of the articles. The research described in this thesis was performed at the Divisions of Molecular Biology and Immunology of the Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital (NKI-AVL), Amsterdam, The Netherlands, and was supported by the Dutch Cancer Society (KWF2011-5004) and the European Research Council (InflaMet 615300).
    [Show full text]
  • Tetanus Toxoid Endo-F
    PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/27226 Please be advised that this information was generated on 2021-09-25 and may be subject to change. 1142 G. D. Keizer, J. Borst, C. G. Figdor et al Eur. J. Immunol. 1985.15: 1142-1147 Gerrit D. Keizer0, Jannie Borst°, Biochemical and functional characteristics of the Carl G. Figdor0 , Hergen Spits0 , Frank MiedemaA, Cox TerhorstD human leukocyte membrane antigen family LFA-1, and Jan E. De Vries0 Mo-1 and pl50,95* Division of Immunology, The Netherlands Cancer Institute (Antoni The human leukocyte function-associated (LFA-1) antigen, the monocyte differentia­ van Leeuwenhoek Huis)0 , Amsterdam, tion antigen Mo-1 which is characterized as the C3bi receptor and the glycoprotein Central Laboratory of the Netherlands p i50,95 are characterized biochemically. Immunoprecipitations carried out with 6 Red Cross Blood Transfusion ServiceA, different monoclonal antibodies (mAb) against LFA-1 indicated that four mAb (SPV- Amsterdam and Dana-Farber Cancer Ll, SPV-L5, SPV-L7 and SPV-L11) were directed against the a chain, whereas mAb Institute0, Boston CLB54 and MHM-23 were found to react with the common |3 chain of LFA-1, Mo-1 and p 150,95. LFA-1 and Mo-1 expressed on KG-1 cells or lymphocytes, monocytes and granulocytes from one donor were homogeneous. Interestingly the a chain of pl50,95 showed heterogeneity. The molecular weight of the a chain expressed on monocytes was consistently higher than that of the a chain on granulocytes.
    [Show full text]
  • Differentiation Antigens of Human Hemopoietic Cells: Patterns of Reactivity of Two Monoclonal Antibodies1
    [CANCER RESEARCH 43, 4812-4815, October 1983] Differentiation Antigens of Human Hemopoietic Cells: Patterns of Reactivity of Two Monoclonal Antibodies1 Silvana Passano,2 Lisabianca Bùttero, Jeffrey Faust, Massimo Trucco, Antonio Palumbo, Luigi Pegoraro, Beverly Lange, Colette Brezin, Jannie Borst, Cox Terhorst, and Giovanni Rovera The Wistar Institute of Anatomy and Biology, Philadelphia, Pennsylvania 19104 [S. P., L. B., J. F., M. T., A. P., G. R.]; The Institute of Internal Medicine, University of Turin, Italy [L. P.]; Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104 [B. L); and The Dana-Farber Cancer Institute, Boston, Massachusetts 02115 [C. B., J. B., C. T.] ABSTRACT terized the surface antigens recognized by 2 monoclonal anti bodies generated by immunizing mice with AML cells. These Two mouse anti-human monoclonal antibodies (S3.13 and antibodies are reactive with a large number of leukemic cell lines S5.7) raised against cells of acute myelogenous leukemia were and have a complex distribution on hemopoietic cells. found to react with antigens expressed on the surface of subsets of monocytes and lymphocytes. MATERIALS AND METHODS S3.13 precipitates a peptide of M, 29,000, and S5.7 precipi tates a peptide of M, 20,000 present on the surface of all the cell Hemopoietic Tissues. Normal peripheral blood and marrow for these types tested. These two surface antigens were distributed on investigations were obtained from healthy volunteer donors and ap proved by the Committee for the Protection of Human Subjects of The discrete subpopulations of normal hemopoietic cells. The anti Wistar Institute. bodies reacted with all (S5.7) or a subpopulation (S3.13) of Mononuclear cells were separated by FicolhHypaque (D = 1.078) peripheral blood T-lymphocytes, and with a subset of monocytes.
    [Show full text]
  • GPA33: a Marker to Identify Stable Human Regulatory T Cells
    The Journal of Immunology GPA33: A Marker to Identify Stable Human Regulatory T Cells Rianne Opstelten,* Sander de Kivit,†,1 Manon C. Slot,* Maartje van den Biggelaar,‡ Dorota Iwaszkiewicz-Grzes,x Mateusz Gliwin´ski,x Andrew M. Scott,{ Bianca Blom,‖ Piotr Trzonkowski,x Jannie Borst,†,1 Eloy Cuadrado,* and Derk Amsen* FOXP3-expressing regulatory T (Treg) cells safeguard immunological tolerance. Treg cells can be generated during thymic development (called thymic Treg [tTreg] cells) or derived from mature conventional CD4+ T cells that underwent TGF-b– mediated conversion in the periphery (called peripheral Treg [pTreg] cells). Murine studies have shown that tTreg cells exhibit strong lineage fidelity, whereas pTreg cells can revert into conventional CD4+ T cells. Their stronger lineage commitment makes tTreg cells the safest cells to use in adoptive cell therapy, increasingly used to treat autoimmune and inflammatory disorders. Markers to distinguish human tTreg cells from pTreg cells have, however, not been found. Based on combined proteomic and transcriptomic approaches, we report that the Ig superfamily protein GPA33 is expressed on a subset of human Treg cells. GPA33 is acquired late during tTreg cell development but is not expressed on TGF-b–induced Treg cells. GPA33 identifies Treg cells in human blood that lack the ability to produce effector cytokines (IL-2, IFN-g, IL-17), regardless of differentiation stage. GPA33high Treg cells universally express the transcription factor Helios that preferentially marks tTreg cells and can robustly and stably be expanded in vitro even without rapamycin. Expanded GPA33high Treg cells are suppressive, unable to produce proinflammatory cytokines, and exhibit the epigenetic modifications of the FOXP3 gene enhancer CNS2, necessary for indelible expression of this critical transcription factor.
    [Show full text]
  • CD70 As an Actionable Immunotherapeutic Target in Recurrent Glioblastoma
    bioRxiv preprint doi: https://doi.org/10.1101/2021.06.02.446670; this version posted June 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Hitting more birds with one stone: CD70 as an actionable immunotherapeutic target in recurrent glioblastoma 1* 2* 1 2 1 2 Seyfrid M , Maich W , Shaikh MV ,Tatari N , Upreti D , Piyasena D , Subapanditha M1, Savage N2, McKenna D1, Kuhlmann L 3, Khoo A3, Salim SK2, Bassey-Archibong B1, Gwynne W1, Chokshi C 2, Brown K4, Murtaza N2, Bakhshinyan D2, Vora P1, Venugopal C1, Moffat J4, Singh SK1,2. *These authors made equal contributions to this paper Departments of 1Surgery, 2Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, 1200 Main Street West, Hamilton, Ontario, L8N 3Z5, Canada 3Princess Margaret’s Hospital, Toronto, Ontario, M5S 3E1, Canada 4Donnelly Centre, Department of Molecular Genetics, University of Toronto, Ontario, Canada RUNNING TITLE CD70 as an immunotherapeutic for recurrent GBM KEYWORDS: Glioblastoma, CD70, Immunotherapy, CAR-T CONFLICTS OF INTEREST: This work was partly funded by Longbow Therapeutics (company no longer in existence) 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.02.446670; this version posted June 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.
    [Show full text]
  • CD27 Sustains Survival of Ctls in Virus-Infected Nonlymphoid Tissue in Mice by Inducing Autocrine IL-2 Production
    CD27 sustains survival of CTLs in virus-infected nonlymphoid tissue in mice by inducing autocrine IL-2 production Victor Peperzak, … , Elise A.M. Veraar, Jannie Borst J Clin Invest. 2010;120(1):168-178. https://doi.org/10.1172/JCI40178. Research Article Immunology Immunity to infections relies on clonal expansion of CD8+ T cells, their maintenance as effector CTLs, and their selection into a memory population. These processes rely on delivery of survival signals to activated CD8+ T cells. We here reveal the mechanism by which costimulatory CD27-CD70 interactions sustain survival of CD8+ effector T cells in infected tissue. By unbiased genome-wide gene expression analysis, we identified the Il2 gene as the most prominent CD27 target gene in murine CD8+ T cells. In vitro, CD27 directed IL-2 expression and promoted clonal expansion of primed CD8+ T cells exclusively by IL-2–dependent survival signaling. In mice intranasally infected with influenza virus,C d27–/– CD8+ effector T cells displayed reduced IL-2 production, accompanied by impaired accumulation in lymphoid organs and in the lungs, which constitute the tissue effector site. Reconstitution of Cd27–/– CD8+ T cells with the IL2 gene restored their accumulation to wild-type levels in the lungs, but it did not rescue their accumulation in lymphoid organs. Competition experiments showed that the IL-2 produced under the control of CD27 supported effector CD8+ T cell survival in the lungs in an autocrine manner. We conclude that CD27 signaling directs the IL-2 production that is reportedly essential to sustain survival of virus-specific CTLs in nonlymphoid tissue.
    [Show full text]