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B Cells + Interaction Human B Cell Activation by Autologous NK Cells Is Regulated by CD40-CD40 Ligand Interaction: Role of Memory B Cells and CD5 + B Cells This information is current as of October 2, 2021. Isaac R. Blanca, Earl W. Bere, Howard A. Young and John R. Ortaldo J Immunol 2001; 167:6132-6139; ; doi: 10.4049/jimmunol.167.11.6132 http://www.jimmunol.org/content/167/11/6132 Downloaded from References This article cites 45 articles, 17 of which you can access for free at: http://www.jimmunol.org/content/167/11/6132.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 October 2, 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 © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Human B Cell Activation by Autologous NK Cells Is Regulated by CD40-CD40 Ligand Interaction: Role of Memory B Cells and CD5؉ B Cells Isaac R. Blanca,*† Earl W. Bere,* Howard A. Young,* and John R. Ortaldo1* NK cells are a subpopulation of lymphocytes characterized primarily by their cytolytic activity. They are recognized as an important component of the immune response against virus infection and tumors. In addition to their cytolytic activity, NK cells also participate either directly or indirectly in the regulation of the ongoing Ab response. More recently, it has been suggested that NK cells have an important role in the outcome of autoimmune diseases. Here, we demonstrate that human NK cells can induce autologous resting B cells to synthesize Ig, including switching to IgG and IgA, reminiscent of a secondary Ab response. B cell activation by the NK cell is contact-dependent and rapid, suggesting an autocrine B cell-regulated process. This NK cell function is T cell-independent, requires an active cytoplasmic membrane, and is blocked by anti-CD40 ligand (anti-CD154) or CD40-mIg Downloaded from fusion protein, indicating a critical role for CD40-CD40 ligand interaction. Depletion studies also demonstrate that CD5؉ B cells autoreactive B-1 cells) and a heterogeneous population of CD27؉ memory B cells play a critical role in the Ig response induced) by NK cells. The existence of this novel mechanism of B cell activation has important implications in innate immunity, B cell- mediated autoimmunity, and B cell neoplasia. The Journal of Immunology, 2001, 167: 6132–6139. lassically, NK cells are characterized by their ability to man NK cells can enhance the B cell proliferative responses to the http://www.jimmunol.org/ lyse transformed cells and virally infected cells without surface Ig cross-linking agents anti-IgM or Staphylococcus aureus previous immunization. Phenotypically mature circulating Cowan strain (6). C Ϫ ϩ ϩ dim NK cells express the CD3 CD56 CD16 CD2 surface markers By direct interaction between B cells and NK cells, it has been and are distinguishable from T cells by the lack of rearranged TCR shown that B cells are able to stimulate the production of IFN-␥ by genes. Unlike B cells, NK cells do not express surface Ig (1). NK cells and activation of the NK cells (11). Thus, both B cells In addition to their cytotoxic activity, NK cells participate either and NK cells are capable of interacting in a spontaneous manner directly or indirectly in multiple developmental and regulatory as- leading to a costimulatory effect. pects of the immune system characterized by rapid response to The evidence described above suggests that NK cells are in- exogenous and endogenous signals by producing a variety of cy- volved in B cell maturation, Ig secretion, and isotype switching, by guest on October 2, 2021 tokines and chemokines (2–4). pathways well-known to be regulated by CD40-CD154 interaction The ability of NK cells to produce hemopoietic cell growth fac- (12). The absence, or blockade, of the CD40-CD154 interaction re- tors, IFN, IL, TNF ␣ and ␤, TGF, and other growth factors, com- sults in gross impairment of the B cell physiological and molecular bined with their ability to respond rapidly to exogenous signals by pathways that seem to be unique to the T-dependent Ab response. up-regulating mRNA expression for various cytokines within minutes Whether the CD40-CD154 engagement plays a role in B cell demonstrates the importance of NK cells as mediators or effectors of regulation by NK cells remains to be clarified. The expression of the intercellular communication network (reviewed in Ref. 2). mRNA for CD40 ligand (CD40L)2 on purified NK cells has been Under activated conditions, NK cells express and up-regulate reported previously (13); more recently, a role for CD40-CD154 in the receptors for a variety of chemotactic factors, cytokines, NK cell interaction with other cells has been described (14). NK growth factors, and hormones including the expression of the li- cell clones expressing CD154 were able to kill target cells express- gand of the CD40 receptor (CD154) thus enhancing NK cell in- ing CD40 receptors. Although freshly isolated human NK cells teractions within the immune system. For example, it has been were unable to lyse CD40ϩ targets, when activated with rIL-2 they shown that NK cells are involved in the regulation of B lympho- were able to kill the CD40-transfected cells. This study also re- cyte functions (5–8). Donor type-activated NK cells promote mar- ported that coexpression of CD40 and MHC class I Ag on the row engraftment and B cell development during allogeneic bone target cell inhibited the lysis by the NK cells, suggesting a regu- marrow transplantation in mice (9) and in humans (10). Also, hu- latory role of MHC class I in the CD40-triggered killing. Direct interaction between B and NK cells under activated con- ditions are supported by several studies, particularly in mouse *Laboratory of Experimental Immunology, Division of Basic Sciences, National Can- models (15–18). Evidence from human studies suggests that NK cer Institute, Frederick, MD 21702; and †Instituto de Inmunologia, Facultad de Me- dicina, Universidad Central de Venezuela, Caracas, Venezuela cells and B cells can spontaneously interact in vitro, as demon- Received for publication May 11, 2001. Accepted for publication September strated by conjugate formation and activation of the interacting 21, 2001. cells (11). However, this activating function is poorly understood. The costs of publication of this article were defrayed in part by the payment of page NK cells are potent regulatory cells in the innate immune sys- charges. This article must therefore be hereby marked advertisement in accordance tem, characterized by their spontaneous interaction with immune with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Address correspondence and reprint requests to Dr. John R. Ortaldo, Laboratory of Experimental Immunology, Center for Cancer Research, Frederick Cancer Research 2 Abbreviations used in this paper: CD40L, CD40 ligand; RT, room temperature; and Development Center, National Cancer Institute, Building 560, Room 31-93, Fred- BsNK, B cells stimulated with NK cells; BsT, B cells stimulated with T cells; BMT, erick, MD 21702-1201. E-mail address: [email protected] bone marrow transplantation. Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 The Journal of Immunology 6133 and nonimmune cells (11, 19). In addition, growing evidence sug- microcentrifuge tubes (Fisher Scientific, Pittsburgh, PA). The cell suspen- gests that NK cells might be involved in the development of au- sion was centrifuged at 200 ϫ g for 10 s in a microcentrifuge (Capsule; toimmune diseases (20). However, the mechanisms by which NK Tomy, Tokyo, Japan) and incubated for 5 min at 37°C in a water bath. Then, cell mixtures were immediately transferred to an ice bath. These cells modulate these responses are not entirely clear. In this study, conditions were previously determined as the minimum time necessary to we tested the hypothesis that spontaneous interaction between hu- activate the B cells with the NK cells as evaluated by tyrosine-phospho- man B cells and autologous NK cells might be important in initi- rylation studies (data not shown). In some experiments, the cell mixture 5 ating the innate B cell response which, under the appropriate con- was only desegregated and the B cell concentration was adjusted to 5 ϫ 10 cells/ml in RPMI 1640 plus 10% FCS (complete medium) and cultured for ditions, might provide an early protective advantage to the host or 6 days at 37°C in an atmosphere of 5% CO2. In other experiments, the contribute to the development of autoimmunity. stimulating T cells or NK cells were removed from the mixture by mag- netic columns (as described above) after labeling at 4°C with biotinylated Materials and Methods anti-CD3 plus streptavidin microbeads or anti-CD56 microbeads, respec- Reagents tively. The remaining B cells stimulated with T cells (BsT cells) or with NK cells (BsNK cells) contained Ͻ2% of T cells or NK cells as determined RPMI 1640 culture medium and Dulbecco’s PBS, L-glutamine, and peni- by flow cytometry using double-labeling with anti-CD5 FITC/anti-CD19 cillin-streptomycin were purchased from BioWhittaker (Walkersville, PE and anti-CD19 FITC/CD16 PE, respectively.
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