DOCSLIB.ORG

Role of Natural Killer Cell Subsets in Cardiac Allograft Rejection

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Role of Natural Killer Cell Subsets in Cardiac Allograft Rejection American Journal of Transplantation 2006; 6: 505–513 ⃝C 2006 The Authors Blackwell Munksgaard Journal compilation ⃝C 2006 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/j.1600-6143.2005.01226.x Role of Natural Killer Cell Subsets in Cardiac Allograft Rejection M. E. McNerneya,†, K.-M. Leeb,†, P. Zhouc,†, Introduction L. Molineroc, M. Mashayekhic, D. Guziora, H. Sattarc, S. Kuppireddia, C.-R. Wanga, Understanding acute allograft rejection is of critical impor- V. Kumara,‡ and M.-L. Alegrec,∗,† tance for achieving successful organ transplant outcomes. In mice, CD4+ T cells are necessary and sufficient for acute + aDepartment of Pathology, The University of Chicago, rejection of cardiac allografts (1–5). Although the CD4 re- Chicago, Illinois, USA sponse is attenuated by disruption of CD28-B7 interaction, bDepartment of Biochemistry and Division of Brain Korea CD28-deficient mice retain the ability to acutely reject car- 21, Program for Biomedical Science, Korea University diac allografts (6–8). This is due to a rejection pathway that, College of Medicine, Seoul, Korea unlike in wild-type recipients, depends on CD4+, CD8+ cDepartment of Medicine, The University of Chicago, T cells (8) and NK1.1+ cells (9). However, the subset and Chicago, Illinois, USA mechanism by which NK1.1+ cells promote rejection re- ∗ Corresponding author: Maria-Luisa Alegre, mains unknown. CD28−/− mice have normal numbers of [email protected] NK and NKT cells. Whereas function of NK cells is normal (10), NKT cells may have impaired cytokine response to To achieve donor-specific immune tolerance to allo- alpha-GalCer (11,12). Thus, either of these NK1.1+ popula- geneic organ transplants, it is imperative to under- tions may contribute to rejection. stand the cell types involved in acute allograft rejec- + tion. In wild-type mice, CD4 T cells are necessary and In this study, we found that NK cells and not NKT cells pro- sufficient for acute rejection of cardiac allografts. How- mote acute rejection of H-2d cardiac grafts in H-2b CD28−/− ever, when T-cell responses are suboptimal, such as in mice. A small subset of NK cells was sufficient to induce mice treated with costimulation-targeting agents or in CD28-deficient mice, and perhaps in transplanted pa- rejection and was regulated by the classical ‘missing-self’ tients taking immunosuppressive drugs, the participa- response characteristic of NK cells. We have previously re- tion of other lymphocytes such as CD8+ T cells and ported that H-2b NK cell rejection of H-2d bone marrow is NK1.1+ cells becomes apparent. We found that host dependent on the H-2Dd-binding activating receptor Ly49D NK but not NKT cells were required for cardiac rejec- (13). Herein, we determined that Ly49D was not required tion. Ly49G2+ NK cells suppressed rejection, whereas a for the NK cell response to H-2d cardiac transplants, sug- subset of NK cells lacking inhibitory Ly49 receptors for gesting that NK cell responses to allogeneic solid organs donor MHC class I molecules was sufficient to promote and bone marrow are markedly different. In addition, we rejection. Notably, rejection was independent of the demonstrate that NK cells promote proliferation and effec- activating receptors Ly49D and NKG2D. Finally, our ex- tor function of alloreactive T cells. periments supported a mechanism by which NK cells promote expansion and effector function of alloreac- tive T cells. Thus, therapies aimed at specific subsets of NK cells may facilitate transplantation tolerance in Materials and Methods settings of impaired T-cell function. Mice Key words: Costimulation, mouse, NK cells, tolerance, C57BL/6 (H-2b), BALB/c (H-2d), C57BL/6 X BALB/c (H-2dxb), RAG-1−/− and transplantation CD28−/− (C57BL/6 background) mice were purchased from Jackson Labo- ratories. CD1−/−/CD28−/− mice (C57BL/6 background) (14) and 2C TCR Tg Received 11 July 2005, revised 31 October 2005 and RAG-1−/− were maintained at the University of Chicago. All experiments accepted for publication 17 November 2005 performed were approved by the University of Chicago Animal Care and Use Committee and according to NIH guidelines. Antibodies Antibodies were injected i.p. Anti-2B4 (20 lL ascitis, days −2 and +3); anti-asialo-GM1 (10 lL ascitis, Wako days −2, +3); anti-Ly49G2 (4D11, 150 lL ascitis, days −2, +1); anti-Ly49C/I (5E6, 100 lL ascitis, days −2, +1); †Equal co-first authors anti-Ly49D (12A8, 200 lg, days −2, +1; or 4E5, 150 lg, days −2, +1); anti- ‡Equal co-senior authors NKG2D (CX5, eBioscience, 133 or 200 lg, days −1, 0, +4) (15). Subset 505 McNerney et al. depletion and NKG2D blockade were always confirmed by PBL FACS anal- ysis. A Ly49G2 (4D11) and Ly49A (YE1/32) mAbs were purified from hy- 6 Untreated Untreated bridomas and fluorescently labeled (University of Chicago). Fluorescent- Anti-2B4 Anti-2B4 labeled mAbs purchased from BD Biosciences were anti-Ly49A (A1), 5 anti-Ly49A/D (12A8), anti-Ly49C/I (5E6), anti-Ly49D (4E5), anti-Ly49I (YLI90), 4 SA-PE, SA-APC and isotype controls. Purified and fluorescently labeled mAbs purchased from eBioscience were anti-NK1.1 (PK136), anti-NKG2D 3 BIO (CX5) and anti-CD3 (145-2C11). Cardiac transplantation 2 The abdominal heterotopic cardiac transplantation protocol was performed as previously described (16). 1 %NK1.1+ CD3- NK cells Flow cytometry 0 Flow cytometry was performed as previously described (17). For analy- Day 3 Day23 sis of heart-infiltrating lymphocytes, cardiac transplants were rinsed in situ Days after treatment with HBSS/heparin, explanted, cut and digested with collagenase IV (Sigma- Aldrich, 400U/mL) and DNase I (MP Biomedicals, 0.01%) in HBSS for 40 min at 37◦C. Mononuclear cells were isolated following density gradient cen- B trifugation over a 44.5% Nycodenz solution, washed and analyzed by FACS. 100 Mixed lymphocyte reaction 80 C57BL/6 NK cells were derived by culture of RAG-1−/− splenocytes as described previously (17). On day 4, NK cells were plated with IL-2 in wells coated with anti-NK1.1 (1 lg/mL) for 2 days, washed extensively and added 60 to MLR cultures. 40 T cells were purified from C57BL/6 lymph nodes by negative selection us- survival % graft ing MACS columns (Miltenyi Biotec). T cells were labeled with CFSE (In- 20 vitrogen, 1 lM, 10 min at 37◦C). c -irradiated (2500 rad) splenocytes (8 × 105/well) were used to stimulate responder T cells (2 × 105/well). NK cells 0 were added at the indicated NK cell:T-cell ratios. 020406080100 IFNc ELISPOTs days post heart transplant ELISPOTs were performed as previously described (16). BALB/c → CD28-/- BALB/c → CD28-/- + anti-asialo-GM1 Statistical analysis BALB/c → CD28-/- + anti-2B4 Differences between mean survival times (MST) were compared using BALB/c → CD28-/-/CD1-/- Kaplan-Meier/log rank test methods. Student’s t-test compared T-cell func- tional readouts. Figure 1: Classical NKT cells are not necessary for cardiac allograft rejection in CD28−/− mice. CD28−/− C57BL/6 mice Results were untreated (n = 7), or treated with anti-asialo-GM1 (n = 4), or anti-2B4 (n = 6) and transplanted with allogeneic BALB/c cardiac Recipient classical NKT cells are not required for grafts. CD1−/−/CD28−/− recipients (n = 6) also received BALB/c + − acute cardiac allograft rejection hearts. (A) The percentage of NK1.1 CD3 NK cells in the periph- −/− It has been reported that NK1.1+ cells are required for eral blood of untreated and anti-2B4-treated CD28 mice was measured on days 3 and 24 after treatment. (B) Allogeneic graft acute cardiac allograft rejection by CD28-deficient mice (9). survival was monitored over time. NK1.1 is expressed on both NK and NKT cells (18–22). To test the role for host NKT cells in acute cardiac allograft rejection we used CD1-deficient mice, which lack classi- Semi-allogeneic cardiac grafts are accepted in cal NKT cells (14). As reported previously using anti-NK1.1 CD28−/− mice (9), depletion of NK and NKT cells using anti-2B4 (23) or NK cells are regulated by MHC class I expression on tar- anti-asialo-GM1 resulted in acceptance of most BALB/c get cells as described in the missing-self hypothesis (24). cardiac grafts by CD28−/− recipients (Figure 1). In con- As such, allogeneic bone marrow transplants are elimi- trast, CD1−/−CD28−/− mice acutely rejected heart trans- nated by NK cells, but semi-identical F1 bone marrow is plants similar to CD28−/− recipients. Therefore, recipient not rejected because of self-MHC coexpression (22). To NKT cells are not required for acute cardiac allograft rejec- confirm a role for NK cells in cardiac allograft rejection, tion in CD28−/− mice. Anti-2B4 treatment did not deplete we transplanted C57BL/6 CD28−/− mice with F1 semi- T cells, as T cells constituted 41 ± 3% of PBLs in control identical hearts. In agreement with a previous report (9), mice and 43 ± 9% in anti-2B4-treated mice. F1 cardiac transplants were accepted by CD28−/− mice but 506 American Journal of Transplantation 2006; 6: 505–513 NK Cells Promote Alloresponses frequency of NK cells within syngeneic transplants hin- 100 dered conclusive assessment of Ly49 receptor expression (Figure 3C). In allogeneic hearts, a higher proportion of NK 80 cells were Ly49D+ on day 6 post-allogeneic transplanta- tion when compared with splenic NK cells (Figure 3C). In 60 contrast, NK cells expressing inhibitory receptors for H- 2Dd were underrepresented in cardiac allografts with fewer 40 than 6% of NK cells expressing Ly49G2, compared to 30% % graft survival in the spleen. Ly49C/I/A were also expressed on a lower 20 fraction of allograft infiltrating NK cells than in the spleen, although differences were less dramatic.
Load more

Recommended publications
  • Autoimmune Encephalomyelitis by NK In
    In Vivo Regulation of Experimental Autoimmune Encephalomyelitis by NK Cells: Alteration of Primary Adaptive Responses This information is current as Robin Winkler-Pickett, Howard A. Young, James M. of September 27, 2021. Cherry, John Diehl, John Wine, Timothy Back, William E. Bere, Anna T. Mason and John R. Ortaldo J Immunol 2008; 180:4495-4506; ; doi: 10.4049/jimmunol.180.7.4495 http://www.jimmunol.org/content/180/7/4495 Downloaded from References This article cites 70 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/180/7/4495.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 27, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology In Vivo Regulation of Experimental Autoimmune Encephalomyelitis by NK Cells: Alteration of Primary Adaptive Responses1,2 Robin Winkler-Pickett,* Howard A. Young,3* James M.
    [Show full text]
  • The Murine Ly49 Family: Form and Function
    ¡ Archivum Immunologiae et Therapiae Experimentalis, 2001, 49¢ , 47–50 £ PL ISSN 0004-069X Review The Murine Ly49 Family: Form and Function A. P. Makrigiannis and S. K. Anderson: Murine Ly49 Family ¤ ANDREW P. M AKRIGIANNIS1 and STEPHEN K. ANDERSON2* 1 2 Laboratory of Experimental Immunology, Division of Basic Sciences, and Intramural Research Support Program, SAIC Frederick, ¥ National Cancer Institute-FCRDC, Frederick, MD 21702-1201, USA Abstract. The activity of natural killer (NK) cells is regulated by surface receptors that recognize class I MHC. ¦ Murine NK cells express a large family of lectin-related receptors (Ly49s) to perform this fu§ nction, while human ¨ NK cells utilize a separate group of proteins containing Ig-related domains (KIRs). Although these receptor © families are not structurally related, the Ly49 family appears to be the functional equivale§ nt of human KIRs, since it uses similar signal transduction pathways for either activation or inhibition of NK cell function. Therefore, lessons learned from the study of the murine MHC class I receptor system may be relevant to hum an NK function. This review summarizes the current state of knowledge of the Ly49 family. Key words: NK cells; MHC class I; receptors; signal transduction; Ly49; gene family. ¨ Natural killer (NK) cells constitute an important 3 extracellular Ig-like domains. In contrast, the mouse facit of the innate immune response against viruses, class I MHC receptors are members of the Ly49 family parasites, intracellular bacteria, and tumor cells31. Un- of type II glycoproteins belonging to the C-type lectin like cells of the adaptive immune system, NK cells do superfamily.
    [Show full text]
  • The Ly49 Gene Family. a Brief Guide to the Nomenclature, Genetics, And
    REVIEW ARTICLE published: 16 April 2013 doi: 10.3389/fimmu.2013.00090 The Ly49 gene family. A brief guide to the nomenclature, genetics, and role in intracellular infection Alan Rowe Schenkel 1*, Luke C. Kingry 1,2 and Richard A. Slayden1 1 Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA 2 Division of Vector Borne Diseases, Centers for Disease Control and Prevention, Fort Collins, CO, USA Edited by: Understanding the Ly49 gene family can be challenging in terms of nomenclature and Claudia Monaco, Catholic University genetic organization. The Ly49 gene family has two major gene nomenclature systems, Rome and Imperial College, UK Ly49 and Killer Cell Lectin-like Receptor subfamily A (klra). Mice from different strains have Reviewed by: varying numbers of these genes with strain specific allelic variants, duplications, dele- Stephen K. Anderson, National Cancer Institute, USA tions, and pseudogene sequences. Some members activate NK lymphocytes, invariant Daisuke Kamimura, Osaka University, NKT (iNKT) lymphocytes and gdT lymphocytes while others inhibit killing activity. One fam- Japan ily member, Ly49Q, is expressed only on myeloid cells and is not found on NK, iNKT, or gd *Correspondence: T cells. There is growing evidence that these receptors may regulate not just the immune Alan Rowe Schenkel, Department of Microbiology, Immunology and response to viruses, but other intracellular pathogens as well. Thus, this review’s primary Pathology, Colorado State University, goal is to provide a guide for researchers first encountering the Ly49 gene family and a 1682 Campus Delivery, Fort Collins, foundation for future studies on the role that these gene products play in the immune CO 820526, USA.
    [Show full text]
  • CD8 T Regulatory Cells Express the Ly49 Class I MHC Receptor and Are
    CD8+ T regulatory cells express the Ly49 Class I MHC receptor and are defective in autoimmune prone B6-Yaa mice Hye-Jung Kima,b, Xuan Wanga, Soroosh Radfara,b, Thomas J. Sproulec, Derry C. Roopenianc, and Harvey Cantora,b,1 aDepartment of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and bDepartment of Pathology, Harvard Medical School, Boston, MA 02115; and cThe Jackson Laboratory, Bar Harbor, ME 04609 Contributed by Harvey Cantor, December 17, 2010 (sent for review November 22, 2010) The immune system includes a subpopulation of CD8+ T cells well as the C57BL/6 (B6)-Yaa substrain (14, 15). The finding that β fi fi equipped to inhibit the expansion of follicular T helper (TFH) cells, 2 microglobulin de ciency and IL-15 receptor de ciency exacer- resulting in suppression of autoantibody production and associ- bate BXSB-Yaa disease suggests that development of this dis- ated lupus-like disease. These CD8+ T regulatory (Treg) cells recog- order might reflect defective CD8+ Treg cell activity (14). We nize Qa-1/peptide complexes on target TFH cells and depend on the found that B6-Yaa mice have increased numbers of TFH and ger- IL-15 cytokine for development and function. Here we show that minal center (GC) B cells at an early age, and that CD8+ Tregs these CD8+ Treg cells express a triad of surface receptors—CD44, from these mice are unable to suppress WT CD4 T cells in adoptive CD122, and the class I MHC receptor Ly49—and account for <5% hosts. We examined the possibility that defects in the development of CD8+ T cells.
    [Show full text]
  • Immunoreceptor Tyrosine-Based Inhibitory Motif–Dependent Functions of an MHC Class I-Specific NK Cell Receptor
    Immunoreceptor tyrosine-based inhibitory PNAS PLUS motif–dependent functions of an MHC class I-specific NK cell receptor Michael D. Berna,b, Diana L. Beckmana, Takashi Ebiharac,1, Samantha M. Taffnera, Jennifer Poursine-Laurentc, J. Michael Whited, and Wayne M. Yokoyamaa,c,2 aDivision of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; bMedical Scientist Training Program, Washington University School of Medicine, St. Louis, MO 63110; cHoward Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110; and dDepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 Contributed by Wayne M. Yokoyama, August 23, 2017 (sent for review July 24, 2017; reviewed by Albert Bendelac and William E. Seaman) Natural killer (NK) cells express MHC class I (MHC-I)-specific recep- inhibitory Ly49s is to “license” or educate NK cells by self–MHC-I tors, such as Ly49A, that inhibit killing of cells expressing self–MHC-I. so that NK cells become competent to be triggered by their acti- Self–MHC-I also “licenses” NK cells to become responsive to activat- vation receptors (8). ing stimuli and regulates the surface level of NK-cell inhibitory re- In addition to inhibiting and licensing NK cells, binding be- ceptors. However, the mechanisms of action resulting from these tween Ly49s and MHC-I influences the surface levels of interactions of the Ly49s with their MHC-I ligands, particularly in Ly49 receptors on NK cells. Binding between Ly49A and H-2Dd vivo, have been controversial. Definitive studies could be derived down-regulates the mean fluorescence intensity (MFI) of Ly49A from mice with targeted mutations in inhibitory Ly49s, but there by flow cytometry (10).
    [Show full text]
  • A Central Role for Ly49 Receptors in NK Cell Memory Andrew Wight, Brendon D
    A Central Role for Ly49 Receptors in NK Cell Memory Andrew Wight, Brendon D. Parsons, Mir Munir A. Rahim and Andrew P. Makrigiannis This information is current as of September 29, 2021. J Immunol 2020; 204:2867-2875; ; doi: 10.4049/jimmunol.2000196 http://www.jimmunol.org/content/204/11/2867 Downloaded from References This article cites 78 articles, 30 of which you can access for free at: http://www.jimmunol.org/content/204/11/2867.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 by guest on September 29, 2021 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 © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. A Central Role for Ly49 Receptors in NK Cell Memory Andrew Wight,* Brendon D. Parsons,† Mir Munir A. Rahim,‡ and Andrew P. Makrigiannis† In the past decade, the study of NK cells was trans- immune response could come online. It was a great surprise, formed by the discovery of three ways these “innate” then, when evidence was presented that showed NK cells immune cells display adaptive immune behavior, in- displaying adaptive, T cell–like behavior.
    [Show full text]
  • Ly49 Receptors: Innate and Adaptive Immune Paradigms
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE REVIEW ARTICLE published:provided 02 April by 2014 Frontiers - Publisher Connector doi: 10.3389/fimmu.2014.00145 Ly49 receptors: innate and adaptive immune paradigms Mir Munir A. Rahim1*, Megan M.Tu 1, Ahmad Bakur Mahmoud 1,2, Andrew Wight 1, Elias Abou-Samra1, Patricia D. A. Lima3 and Andrew P.Makrigiannis 1 1 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada 2 College of Applied Medical Sciences, Taibah University, Madinah Munawwarah, Kingdom of Saudi Arabia 3 Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada Edited by: The Ly49 receptors are type II C-type lectin-like membrane glycoproteins encoded by a Linde Meyaard, University Medical family of highly polymorphic and polygenic genes within the mouse natural killer (NK) gene Center Utrecht, Netherlands complex.This gene family is designated Klra, and includes genes that encode both inhibitory Reviewed by: Janos G. Filep, University of and activating Ly49 receptors in mice. Ly49 receptors recognize class I major histocompat- Montreal, Canada ibility complex-I (MHC-I) and MHC-I-like proteins on normal as well as altered cells. Their T. Sakari Jokiranta, University of functional homologs in humans are the killer cell immunoglobulin-like receptors, which rec- Helsinki, Finland ognize HLA class I molecules as ligands. Classically, Ly49 receptors are described as being *Correspondence: expressed on both the developing and mature NK cells. The inhibitory Ly49 receptors are Mir Munir A. Rahim, Department of Biochemistry, Microbiology and involved in NK cell education, a process in which NK cells acquire function and tolerance Immunology, University of Ottawa, toward cells that express “self-MHC-I.” On the other hand, the activating Ly49 receptors Roger Guindon Hall, Room 4226, 451 recognize altered cells expressing activating ligands.
    [Show full text]
  • Expansion and Function of CD8 T Cells Expressing Ly49 Inhibitory
    The Journal of Immunology Expansion and Function of CD8؉ T Cells Expressing Ly49 Inhibitory Receptors Specific for MHC Class I Molecules1 Nicolas Anfossi,* Scott H. Robbins,† Sophie Ugolini,* Philippe Georgel,‡ Kasper Hoebe,‡ Ce´cile Bouneaud,§ Catherine Ronet,§ Arthur Kaser,¶ Catherine B. DiCioccio,ʈ Elena Tomasello,* Richard S. Blumberg,¶ Bruce Beutler,‡ Steven L. Reiner,ʈ Lena Alexopoulou,# Olivier Lantz,** David H. Raulet,†† Laurent Brossay,† and Eric Vivier2* MHC class I-specific Ly49 inhibitory receptors regulate NK cell activation, thereby preventing autologous damage to normal cells. ,Ly49 receptors are also expressed on a subset of CD8؉ T cells whose origin and function remain unknown. We report here that despite their phenotypic and cytolytic similarities, Ly49؉CD8؉ T cells and conventional Ly49؊CD44high memory-phenotype CD8؉ T cells present strikingly distinct features. First, under steady state conditions Ly49؉CD8؉ T cells are poor cytokine producers (TNF-␣ and IFN-␥) upon TCR triggering. Second, Ly49؉CD8؉ T cells are not induced upon various settings of Ag immunization or microbial challenge. However, Ly49 can be induced on a fraction of self-specific CD8؉ T cells if CD4؉ T cells are present. Finally, the size of the Ly49؉CD8؉ T cell subset is selectively reduced in the absence of STAT1. These results indicate that Ly49 expression is associated with a differentiation program of cytolytic CD8؉ T cells triggered upon chronic antigenic exposure. They further suggest that the size of the Ly49؉CD8؉ T cell subset marks a history of CD8؉ T cell activation that might preferentially result from endogenous inducers of inflammation rather than from microbial infections.
    [Show full text]
  • Gene-Targeted Mice of Mice
    The Journal of Immunology Aberrant DAP12 Signaling in the 129 Strain of Mice: Implications for the Analysis of Gene-Targeted Mice1 Daniel W. McVicar,2† Robin Winkler-Pickett,† Lynn S. Taylor,† Andrew Makrigiannis,† Michael Bennett,‡ Stephen K. Anderson,* and John R. Ortaldo† NK cells are implicated in antiviral responses, bone marrow transplantation and tumor immunosurveillance. Their function is controlled, in part, through the Ly49 family of class I binding receptors. Inhibitory Ly49s suppress signaling, while activating Ly49s (i.e., Ly49D) activate NK cells via the DAP12 signaling chain. Activating Ly49 signaling has been studied primarily in C57BL/6 mice, however, 129 substrains are commonly used in gene-targeting experiments. In this study, we show that in contrast to C57BL/6 NK cells, cross-linking of DAP12-coupled receptors in 129/J mice induces phosphorylation of DAP12 but not calcium mobilization or cytokine production. Consistent with poor-activating Ly49 function, 129/J mice reject bone marrow less efficiently than C57BL/6 mice. Sequence analysis of receptors and DAP12 suggests no structural basis for inactivity, and both the 129/J and C57BL/6 receptors demonstrate normal function in a reconstituted receptor system. Most importantly, reconstitution of Ly49D in 129/J NK cells demonstrated that the signaling deficit is within the NK cells themselves. These unexpected findings bring into question any NK analysis of 129/J, 129Sv, or gene-targeted mice derived from these strains before complete backcrossing, and provide a possible explanation for the differences observed in the immune response of 129 mice in a variety of models. The Journal of Immunology, 2002, 169: 1721–1728.
    [Show full text]
  • Specific for MHC Class I Molecules Expressing Ly49 Inhibitory
    Expansion and Function of CD8+ T Cells Expressing Ly49 Inhibitory Receptors Specific for MHC Class I Molecules This information is current as Nicolas Anfossi, Scott H. Robbins, Sophie Ugolini, Philippe of September 28, 2021. Georgel, Kasper Hoebe, Cécile Bouneaud, Catherine Ronet, Arthur Kaser, Catherine B. DiCioccio, Elena Tomasello, Richard S. Blumberg, Bruce Beutler, Steven L. Reiner, Lena Alexopoulou, Olivier Lantz, David H. Raulet, Laurent Brossay and Eric Vivier Downloaded from J Immunol 2004; 173:3773-3782; ; doi: 10.4049/jimmunol.173.6.3773 http://www.jimmunol.org/content/173/6/3773 http://www.jimmunol.org/ References This article cites 59 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/173/6/3773.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 28, 2021 • 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 © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Expansion and Function of CD8؉ T Cells Expressing Ly49 Inhibitory Receptors Specific for MHC Class I Molecules1 Nicolas Anfossi,* Scott H.
    [Show full text]
  • Genomic and Functional Analysis of Mouse Ly49 Natural Killer Cell Receptor Genes
    GENOMIC AND FUNCTIONAL ANALYSIS OF MOUSE LY49 NATURAL KILLER CELL RECEPTOR GENES by KARINA LEE McQUEEN B.Sc, The University of Guelph, 1995 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Medical Genetics; Genetics: Graduate Program) We accept this thesis as ccjiibH»ipg to the required standard THE UNIVERSITY OF BRITISH COLUMBIA March 2001 © Karina Lee McQueen, 2.00\ In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of meci^QaX Gyg.ng.'KcS. The University of British Columbia Vancouver, Canada Date YAOLCCK Ql-, QLQOI Abstract The overall objective of my research has been to better understand the genomic complexity of the mouse Ly49 multigene family, which encodes receptors for MHC class I molecules on natural killer (NK) cells. When I began my study, nine Ly49 genes, Ly49a-i, had been identified in the C57BL/6 (B6) mouse, though Southern blot analysis suggested the existence of additional Ly49 genes. To characterize and localize new Ly49 genes, we isolated and mapped PI genomic clones hybridizing to an Ly49c-related probe.
    [Show full text]
  • Regulation of NK Cell Responsiveness to Achieve Self-Tolerance And
    Nathalie T. Joncker Regulation of NK cell David H. Raulet responsiveness to achieve self-tolerance and maximal responses to diseased target cells Authors’ addresses Summary: Inhibitory receptors specific for major histocompatibility com- Nathalie T. Joncker1,2, David H. Raulet1,2 plex (MHC) class I molecules govern the capacity of natural killer (NK) cells 1Department of Molecular and Cell Biology, University of to attack class I-deficient cells (‘missing-self recognition’). These receptors California Berkeley, Berkeley, CA, USA. are expressed stochastically, such that the panel of expressed receptors 2Cancer Research Laboratory, University of California varies between NK cells. This review addresses how the activity of NK cells Berkeley, Berkeley, CA, USA. is coordinated in the face of this variation to achieve a repertoire that is self- tolerant and optimally reactive with diseased cells. Recent studies show that Correspondence to: NK cells arise in normal animals or humans that lack any known inhibitory David H. Raulet receptors specific for self-MHC class I. These NK cells exhibit self-tolerance Department of Molecular and Cell Biology and exhibit functional hyporesponsiveness to stimulation through various 485 LSA activating receptors. Evidence suggests that hyporesponsiveness is induced University of California Berkeley because these NK cells cannot engage inhibitory MHC class I molecules and Berkeley, CA 94720-3200, USA are therefore persistently over-stimulated by normal cells in the environ- Tel.: 510 642 9521 ment. Finally, we discuss evidence that hyporesponsiveness is a quantitative Fax: 510 642 1443 trait that varies depending on the balance of signals encountered by e-mail: [email protected] developing NK cells.
    [Show full text]