Cytokines and B Lymphocytes PDF
Preview Cytokines and B Lymphocytes
Cytokines and Β Lymphocytes edited by R. E. CALLARD Institute of Child Health, London, WC1N1EH ACADEMIC PRESS Harcourt Brace Jovanovich, Publishers London San Diego New York Boston Sydney Tokyo Toronto ACADEMIC PRESS LIMITED 24-28 Oval Road London NW1 7DX United States Edition published by ACADEMIC PRESS INC. San Diego, CA 92101 Copyright © 1990 by ACADEMIC PRESS LIMITED All Rights Reserved No part of this book may be reproduced in any form by photostat, microfilm, or any other means, without written permission from the publishers. ISBN 0-12-155145-8 Typeset by Paston Press, Loddon, Norfolk and printed in Great Britain by Galliard (Printers) Ltd, Great Yarmouth, Norfolk List of contributors Mark R. Alderson Immunex Corporation, 51 University Street, Seattle, Washington 98101, USA. Richard J. Armitage Immunex Corporation, 51 University Street, Seattle, Washington 98101, USA. Jacques Bancherau Schering-Plough (UNICET), Laboratory for Im munological Research, 27 Chemin des Peupliers, 69570 Dardilly, France. Jean-Yves Bonnefoy Glaxo Institute for Molecular Biology, 46 Route des Acacias, 1211 Geneva 24, Switzerland. Robin E. Callard Department of Immunology, Institute of Child Health, 30 Guildford Street, London WC1N 1EH, UK. Thierry DeFrance Schering-Plough (UNICET), Laboratory for Immuno logical Research, 27 Chemin des Peupliers, 69570 Dardilly, France. D. Mark Estes Department of Microbiology, The University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Anto nio, Texas 78284-7758, USA. Andrew J. H. Gearing British Biotechnology, Watlington Road, Cowley Road, Oxford, OX4 5LY, UK. John Gordon Department of Immunology, The Medical School, Vincent Drive, Birmingham, B15 2TJ, UK. Kenneth H. Grabstein Immunex Corporation, 51 University Street, Seattle, Washington 98101, USA. Margaret Harnett Division of Immunology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK. Kevin Rigley Department of Immunology, Institute of Child Health, 30 Guildford Street, London, WC1N 1EH, UK. vii viii List of contributors Sergio Romagnani Department of Clinical Immunology and Allergology, University of Florence, Institute di Clinica, Medica 3, Policclinico di Careggi, 50134 Firenze, Italy. Virginia M. Sanders NIEHS, mail-drop Cl-04, PO Box 12233, Research Triangle Park, North Carolina 27709, USA. John G. Shields Glaxo Institute for Molecular Biology, 46 Route des Acacias, 1211 Geneva 24, Switzerland. Judy M. Teale Department of Microbiology, The University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Anto nio, Texas 78284-7758, USA. Ellen S. Vitetta Department of Microbiology, University of Texas, South western Medical Center, Dallas, Texas 75235, USA. 1 Introduction ROBIN E. CALLARD Aims of this book It is common in books about cytokines to describe in detail the physico- chemical and biological properties of each one in turn, rather than discuss the way in which they interact with a particular physiological system or tissue. This is not the approach taken here. Instead, the emphasis through out is on how cytokines, in combination with other activation signals, regulate Β cell growth and subsequent differentiation into antibody-forming cells. One chapter is devoted to the physico-chemical properties of the different cytokines and their receptors, as this information is not available from any other single reference source. The rest of the chapters deal individually with Β cell activation, proliferation, differentiation, T-B cell collaboration, isotype selection, autocrine stimulation, the role of cytokines in disease, and Β cell assays for cytokines. In each case, responses of both human and murine Β cells are considered so that both their similarities and their differences are made clear. For the most part, only cytokines which have been cloned and fully characterized are included in this book. This is mainly to avoid the uncer tainties and ambiguities associated with the less well characterized factors, but also because now is an appropriate time to summarize the many discoveries made with recombinant cytokines over the past few years. A brief historical perspective The regulation of antibody responses has been a major subject of investi gation for about a hundred years. During this time, there have been a number of significant milestones that have led to our current understanding and point to the direction for future research. Before the discovery of Τ cells and Β cells in the late 1960s, investigations into the regulation of antibody CYTOKINES AND Β LYMPHOCYTES Copyright © 1990 by Academic Press, London ISBN 0-12-155145-8 All rights of reproduction in any form reserved. 2 R. Ε. Callard responses were mostly concerned with the roles of antigen, antibody, and antigen-antibody complexes. At this time, the animal was treated largely as a "black box", with little understanding of the cellular mechanisms under lying immunoregulation. It was not until the small lymphocyte was un equivocally shown to be the precursor to antibody-secreting cells (Gowans and McGregor, 1965; Gowans and Uhr, 1966), and the discovery that Τ cell collaboration was required for optimal antibody responses by Β cells (Claman etal., 1966; Miller and Mitchell, 1968; Mitchell and Miller, 1968), that cellular models of immunoregulation came into fashion. These import ant findings triggered an explosion of cellular regulation studies during the 1970s, culminating in the extremely complex and sometimes bizarre network models of interacting Τ cells to account for help and suppression of antibody responses. The main achievement of this period was to recognize that immuno regulation depended on complex cellular interactions. However, the way in which the participating cells communicated was not known, and in the end the various models failed because they did not address immunoregulation at a molecular level. With the realization that Τ cells can exert their influence on Β cells by defined molecular entities (cytokines and cell surface inter action molecules), immunoregulation entered the molecular era. In the space of 10 years, more than a dozen cytokines that regulate Β cell growth and differentiation have been identified. Although, in some ways, the complexities of cytokine biology have even exceeded the byzantine nature of the cellular network theories, the application of cDNA and gene cloning techniques has allowed precise definition of both the molecules concerned and their cell-surface receptors. These advances have opened the way to investigations of the transmembrane signalling events, intracellular bio chemistry and specific gene regulation, which ultimately determine how any one Β cell will respond to the combination of molecular signals received at the cell surface. Cytokine models of Β cell growth and differentiation In the past, it has been common to think of Β cell differentiation as a linear transition from a homogeneous population of resting Β cells to antibody- secreting cells (Figure 1). According to this model, ligand (antigen or anti- Ig) binding to surface Ig primes the Β cell for subsequent and discrete phases of proliferation and maturation in response to specific growth and differen tiation signals. This simple model has been useful, but is now clearly inadequate to account for the complexity and diversity of Β cell responses. It is now known that many different signals in various synergistic and/or Introduction 3 Linear model of Β cell differentiation antigen Ν- resting Β cell antibody forming cell Τ cells (subsets) accessory ceils cytokines Figure 1 In early models, Β cell differentiation was represented by a linear transition from a homogeneous population of Β cells stimulated by antigen into antibody-forming cells, with each discrete step of proliferation and differen tiation regulated by Τ cells, accessory cells and cytokines. Regulation of Β cell responses • antigen presentation • clonal expansion • antibody secretion • isotype switching • apoptosis - affinity maturation • memory • tolerance • recirculation Functional surface molecules • tissue localisation (Slg, CD20, CD19etc.) Figure 2 It is now known that Β cells can respond in a number of different ways as illustrated. Each response is regulated by signals received at the cell surface from regulatory Τ cells, cytokines, and other ligands binding to functional cell- surface molecules. Cognate Τ cell interactions are known to involve Τ cell- receptor recognition of antigen, in association with MHC class II antigens, CD4 binding to non-polymorphic determinants on MHC class II, LFA-1 binding to ICAM-1/ICAM-2, and CD2 binding to LFA-3. In each case binding seems able to deliver a specific signal to the Β cell. The other functional cell surface antigens (CD19, CD20, etc.) are known to be signal transducing molecules, but their natural ligands are so far unknown. 4 R. E. Callard inhibitory combinations are received at the Β cell surface from interactions with Τ cells, cytokines and other ligands (Figure 2). It is also important to appreciate that Β cell responses are far more diverse and complex than had previously been recognized. In addition to proliferation and differentiation into antibody-secreting cells, many other functions—such as antigen presen tation by Β cells, antibody affinity maturation, generation of memory, tolerance, re-circulation, and microenvironmental localization—must also be subject to regulation (Figure 2). When this complexity is taken into account, it is clear why earlier efforts to understand Β cell regulation in terms of interacting Τ cell subsets were not very successful. Cytokines play only a part in these diverse Β cell responses and must not be considered in isolation. Interactions with other signals delivered by ligand binding to functional cell-surface antigens are also important for determining Β cell responses (Valentine et al., 1988; Brown et al., 1989). Moreover, any one cytokine may have different (enhancing and inhibiting) effects depending on what other signal the cell has received. For example, interferon γ (IFN-y) can induce proliferation by Β cells stimulated with anti- IgM (Romagnani et al., 1986; Defrance et al., 1986), or inhibit Β cell responses to interleukin 4 (Rabin et al., 1986a). Similarly, interleukin 4 (IL-4) activates Β cells and promotes Β cell proliferation (Paul and Ohara, 1987), but inhibits Β cell responses to IL-2 (Defrance etal., 1988; Llorente et al, 1989). Most in vitro techniques for investigating cytokine action on Β cell growth and differentiation require co-stimulation of Β cells with, for example, anti- Ig, to polyclonally mimic the action of antigen. The rationale behind this approach is the idea that activation through surface Ig in combination with Τ cell-derived cytokines is a model for Τ cell help to antigen-stimulated Β cells. To my mind there are two major problems with this model. First, it seems unlikely that the conditions employed to stimulate Β cells with polyclonal crosslinking ligands (anti-Ig, dextran sulphate, lipopoly- saccharide, Staphylococcus aureus Cowan I, etc.) in any way reflects the nature or local concentrations of most Τ cell-dependent antigens presented to Β cells in vivo. In fact, concentrations of rabbit anti-Ig up to 1,000-fold less th-a1n required in co-stimulat-io1n assays with Β cell growth factors (10 ng ml compared with 10//g ml ) have been used successfully with rabbit Ig-specific Τ cell lines to stimulate Β cell immunoglobulin production (Ton-y1 and Parker, 1985). Interestingly, very low doses of anti-Ig (lOOpgml ), when coupled to dextran, are also able to stimulate Β cell responses (Brunswick et al., 1988), but without activation of the phosphoinositide signalling pathway (Brunswick et al., 1989). Secondly, it is now known that antigen binding to Β cell surface Ig is Introduction 5 internalized, processed and then re-expressed on the surface in association with major histocompatibility complex (MHC) class II for presentation to Τ cells (Gosselin et al., 1988; Lanzavecchia, 1988). Proliferation and differen tiation occur after this step in response to signals delivered by Τ cells and Τ cell-derived cytokines (Figure 3). This model is supported by a recent study, in which co-stimulation of quiescent Β cells with anti-Ig and IL-4 was shown to prime Β cells to proliferate in response to subsequent stimulation with immobilized antibodies to MHC class II plus additional cytokines (IL-4, IL-5 and mixed lymphocyte reaction (MLR) supernatant) (Cambier and Lehman, 1989). These results suggest that the combination of signals delivered by antigen (or anti-Ig) and IL-4 may induce quiescent Β cells to process antigen for presentation to Τ helper cells, rather than stimulate proliferation and differentiation. In typical co-stimulation assays with high dose anti-Ig and cytokines, this important antigen-presenting step is not taken into account. Activation of Β cells with IL-4 results in increased MHC class II expres sion (Noëlle et al., 1984; Rousset, 1988), which may enhance cognate interactions with Τ cells. Surface IgM expression is also greatly increased (10-fold) on human Β cells activated with IL-4 (Shields et al., 1989). Of particular interest is the dose of IL-4 required for this effect. Whereas 50% maximum expression of Β cell surface CD23, and proliferation of Β cells in-1 co-stimulation assays with anti-IgM, was obtained with about 10 units ml of IL-4, half maximal stimulation of surface IgM expression -w1as obtained with less than one-tenth of this IL-4 dose (about 0.2 units ml ) (Callard et al., 1990). This result shows that IL-4 can have a pronounced effect on Β cells at doses too low for proliferation. Whether activation by low concen trations of IL-4 enhances Β cell antigen presentation or whether it serves some other function has yet to be determined. Cytokines in specific antibody responses Most of what we know about the action of cytokines on Β cells has come from studies with polyclonal activators such as anti-Ig, lipopolysaccharide (LPS), SAC or phorbol myristate acetate (PMA). As a result, very little is known about the function of cytokines in specific antibody responses. IL-5 is a Τ cell replacing factor (TRF) for specific antibody responses in mice (Takatsu et al., 1988) whereas IL-2 (but not IL-5) is a TRF in man (Callard et al., 1986; Delfraissy et al., 1988). However, IL-2 is only a TRF for low/medium density Β cells and is unable to restore antibody production by high density "resting" Β ceils (Callard and Smith, 1988). Overnight incu- 6 R. Ε. Callard Antigen Presentation Proliferation Differentiation Figure 3 In antibody responses to Τ cell-dependent antigens, Β cells first internalize, process, and re-express antigen in association with MHC class II antigens for presentation to Τ helper cells. This step may be regulated by IL-4. Subsequently, interaction with Τ cells and Τ cell derived cytokines (IL-2 in humans) results in proliferation and maturation into specific antibody-forming cells (AFC). bation with antigen and Τ cells converted high-density Β cells to IL-2 responders, suggesting that resting Β cells stimulated with T-dependent antigens must receive a signal from Τ helper cells before they are able to respond to cytokines (in this case IL-2) and differentiate into antibody secreting cells. Immunoglobulin production by human Β cells stimulated with IL-2 and SAC was recently reported to be mediated by autocrine production of IL-6 (Xia et al., 1989). Similarly, IL-6 has been shown to be essential for polyclonal Ig secretion in response to pokeweed mitogen (PWM) (Muragu- chi et al., 1988). In contrast to these findings, we have shown recently that although IL-6 sometimes enhances specific antibody responses to influenza virus by human tonsillar lymphocytes, a blocking IL-6 antibody had no effect showing that IL-6 is not required for this response (Callard et al., 1990). In the mouse, IL-6 is required for production of specific antibody to influenza virus by naïv e (unprimed) Β cells but not by primed Β cells (Hubert et al., 1989), which is consistent with our findings in human (primed) responses to influenza virus. In humans at least, IL-2 seems sufficient for Β cell proliferation and differentiation into antibody-forming cells after initial activation by antigen and Τ helper cells. This raises important questions about the function of
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