B-lymphocyte Differentiation

176 Pages·2017·14.58 MB·English

by  John C. Cambier

B-Lymphocyte
Differentiation
Editor
John C . Cambier, Ph.D.
Member
Department of Medicine/Division of Basic Immunology
National Jewish Center for Immunology and Respiratory Medicine
Denver, Colorado
Boca Raton London New York
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Library of Congress Cataloging in Publication Data
Main entry under title:
B-lymphocyte differentiation.
Includes bibliography and index.
1. B lymphocytes. 2. Cell differentiation. I. Cambier,
John C., 1948- .
QR185.8.L9B19 1986 616.07’9 85-12726
ISBN-0-8493-5 172-3
A Library of Congress record exists under LC control number: 85012726
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THE EDITOR
John C. Cambier, Ph.D,, is Member, Department of Medicine/Division of Basic
Immunology, National Jewish Center for Immunology and Respiratory Medicine and
is Associate Professor, Department of Microbiology and Immunology, University of
Colorado Health Sciences Center, Denver, Colorado.
As a doctoral student in 1974, Dr. Cambier served as a Fellow at the Max-Planck-
Institute fur Tierzucht und Tierernahrung, Mariensee, West Germany assisting in the
establishment of a research program designed to examine the importance of breast
feeding in the protection of infants against diarrheal diseases. He received his Ph.D. in
1975 from the University of Iowa in Immunology-Virology. From 1975 to 1978 he
served as an NIH postdoctoral fellow and then as an instructor at the University of
Texas Health Science Center. Dr. Cambier held various positions at Duke University
Medical Center from 1978 to 1983, including Adjunct Associate Professor in the De-
partment of Microbiology and Immunology. During that time he was a Visiting Sci-
entist at Bundesforschungsanstalt fur Tierzucht und Tierverhalten, Neustadt, West
Germany. He has been on the staff of the National Jewish Center for Immunology
and Respiratory Medicine and the University of Colorado since 1983.
Dr. Cambier has been the recipient of the National Research Service and the Re-
search Career Development awards and is a member of the American Association of
Immunologists, the Flow Cytometry Society, and the NSF Cell Physiology Panel.
He has authored or CO-authoredm ore than 50 scientific publications. His major
research interests include lymphocyte activation and regulation, stem cell regulation,
and flow cytometry.
CONTRIBUTORS
Larry W. Arnold, Ph.D. Fred Finkelman, M.D.
Research Assistant Professor Director
Department of Microbiology and Division of Rheumatology and
Immunology Immunology
University of North Carolina Associate Professor
Chapel Hill, North Carolina Department of Medicine
Uniformed Services University of the
Gail A. Bishop, Ph.D. Health Sciences
Postdoctoral Fellow Bethesda, Maryland
Department of Microbiology and
Immunology
University of North Carolina Geoffrey Haughton, Ph.D.
Chapel Hill, North Carolina Professor of Immunology
Department of Microbiology and
Immunology
John C. Cambier, Ph.D.
University of North Carolina
Member
Chapel Hill, North Carolina
Department of Medicine/Division of
Basic Immunology
National Jewish Center for
Immunology and Respiratory John W. Kappler, Ph.D.
Medicine Associate Professor
Associate Professor of Microbiology Department of Medicine
and Immunology National Jewish Center for
University of Colorado Immunology and Respiratory
Denver, Colorado Medicine
Denver, Colorado
K. Mark Coggeshall, Ph.D.
Department of Pharmacology
David E. Lafrenz, Ph.D.
Washington University School of
Research Scientist
Medicine
Research & Development
St. Louis, Missouri
Veterans Administration Medical
Center
Ronald B. Corley, Ph.D. Iowa City, Iowa
Associate Professor
Department of Microbiology and
Immunology H. James Leibson
Duke University Medical Center Department of Medicine
Durham, North Carolina National Jewish Center for
Immunology and Respiratory
Medicine
Thomas L. Feldbush, Ph.D. Denver, Colorado
Professor
Departments of Microbiology and Nicola J. LoCascio, Ph.D.
Urology Research Assistant
University of Iowa Department of Microbiology and
Veterans Administration Medical Immunology
Center University of North Carolina
Iowa City, Iowa Chapel Hill, North Carolina
Paula M. Lutz, Ph.D. Christopher A. Pennell, B.S.
Department of Microbiology and Research Assistant
Immunology Department of Microbiology and
University of North Carolina Immunology
Chapel Hill, North Carolina University of North Carolina
Chapel Hill, North Carolina
Phillippa Marrack, Ph.D.
Associate Professor Beverley L. Pike, Ph.D.
Department of Medicine Cellular Immunology Unit
National Jewish Center for The Walter and Eliza Hall Institute of
Immunology and Respiratory Medical Research
Medicine Victoria, Australia
Denver, Colorado
John T. Ransom
Eleanor S. Metcalf, Ph.D. National Jewish Center for
Associate Professor Immunology and Respiratory
Department of Microbiology Medicine
Uniformed Services University of the Denver, Colorado
Health Sciences
Bethesda, Maryland Neal Roehm, Ph.D.
Research Associate
James J. Mond, Ph.D., M.D. Department of Medicine
Associate Professor National Jewish Center for
Department of Medicine Immunology and Respiratory
Uniformed Services University of the Medicine
Health Sciences Denver, Colorado
Bethesda, Maryland
Laura L. Stunz, Ph.D.
John G. Monroe Graduate Student
Department of Medicine Department of Microbiology
Tufts New England Medical Center University of Iowa
Boston, Massachusetts Iowa City, Iowa
Professor Sir Gustav J. V. Nossal, Dorothy Yuan, Ph.D.
F.A.A., F.R.S. Assistant Professor
Director Department of Pathology
The Walter and Eliza Hall Institute of University of Texas Health Sciences
Medical Research Center
Victoria, Australia Dallas, Texas
Albert Zlotnik, Ph.D.
Staff Scientist
DNAX Research Institute of Molecular
Cellular Biology
Palo Alto, California
TABLE OF CONTENTS
Chapter 1
Mechanisms of Transmembrane Signal Transduction During B-Cell Activation.. ..... 1
K. Mark Coggeshall, John G. Monroe, John T. Ransom, and John C. Cambier
Chapter 2
Regulation of Gene Expression During B-Cell Differentiation ............................ 23
Dorothy Yuan
Chapter 3
Anti-Immunoglobulin Antibody Induction of B-Lymphocyte Activation and
Differentiation In Vivo and In Vitro ............................................................. 41
Fred D. Finkelman, James J. Mond, and Eleanor S. Metcalf
Chapter 4
Helper Signals in B-Lymphocyte Differentiation .............................................. 61
Neal W. Roehm, H. James Leibson, Albert Zlotnik, Phillippa Marrack,
and John W. Kappler
Chapter 5
Growth and Differentiation of B-Cell Clones In Vitro ...................................... 79
Beverley L. Pike and G. J. V. Nossal
Chapter 6
B-Cell Tumors as Models of B-Lymphocyte Differentiation .............................1 09
Larry W. Arnold, Paula M. Lutz, Christopher A. Pennell, Gail A. Bishop,
Ronald B. Corley, Geoffrey Haughton, Nicola J. LoCascio
Chapter 7
Memory B-Cell Activation, Differentiation, and Isotype Switching ....................1 35
Thomas L. Feldbush, Laura L. Stunz, and David E. Lafrenz
Index.. ................................................................................................. 163
Chapter 1
MECHANISMS OF TRANSMEMBRANE SIGNAL TRANSDUCTION
DURING B CELL ACTIVATION
K . Mark Coggeshall. John G . Monroe.
. .
John T Ransom. and John C Cambier
TABLE OF CONTENTS*
I . Introduction .................................................................................... 2
I1 . Transmembrane Signaling Mechanisms ................................................. 3
A . Protein Phosphorylation ........................................................... 3
B . Cyclic Nucleotides ................................................................... 4
C . Calcium ................................................................................ 5
I11 . Membrane Immunoglobulin-Mediated Transmembrane Signaling ............... 6
A . Membrane Depolarization and mIa Expression .............................. 7
B . Protein Kinase C and Membrane Depolarization ............................ 7
C . Phosphatidylinositol Metabolism and mIg Signaling ........................ 9
D . Ca++M obilization and B Cell Activation ....................................... 9
E . The Model ............................................................................ l l
IV . Future Directions ............................................................................ 14
A . Ig Cross-Linking - PI Hydrolysis Coupling ................................. 15
B . IgM vs . IgD-Mediated Signaling ................................................ 16
C . Transmembrane Signaling by BCGF, Receptors ............................ 16
References .............................................................................................. 18
*
Abbreviations used: PKC. protein kinase C; PMA. phorbol myristate acetate; DAG. diacylglycerol;
PLC. phospholipase C; IP. inositol I-monophosphate; IP.. inositol 1. 4.bisphosphate. IP.. inositol 1.4. 5.
trisphosphate; PI. phosphatidylinositol; PIP. phosphatidylinositol4-phosphate; PIP.. phosphatidylinos-
it01 4.5.bi +phosphate. PA. phosphatidic acid; PS. phosphatidylserine; PC. phosphatidylcholine;
BCGF.. B cell growth factor 1 .
B-Lymphocyte Differentiation
I. INTRODUCTION
It has become clear over the past decade that generation of humoral immune re-
sponses to most antigens requires the productive interaction of at least three cell types,
a number of soluble cell-derived effector molecules, and antigen. The initial B cell
ligand interaction in the generation of thymus-dependent immune responses appears
to be antigen binding by membrane immunoglobulin (mIg) of two classes, mIgM and
m1gD.l The effect of antigen binding is twofold. MIg cross-linking leads to antigen
endocytosis, processing, and reexpression.* Apparently independent of endocytosis,
mIg cross-linking results in generation and transmembrane transduction of signals
which drive the quiescent Go B cell into a poised state characterized by up to a 50-fold
higher expression of surface Ia In this state, which we refer to as Go*, B
cells are optimally prepared to interact with Ia region-restricted and antigen-specific
helper T cells.5 The interaction of Go* B cells with antigen-specific Ia-restricted T cells
results in a further cascade of poorly defined intracellular events which culminates in
transition of these cells into the G, phase of the cell cycle or blast~genesis.I~n the
presence of nonantigen-specific factors which support proliferation, including IL2,
IL1, and BCGF(s), and differentiation, including IFNy, BCDFp, and BCDFy, anti-
body-secreting cells are generated (for a review, see Chapter 4).
As the preceding discussion illustrates, B cells must have the ability to distinguish
and respond differently to a large number of external regulatory species. This presents
the cell with a significant dilemma since there are probably a limited number of bio-
chemical mechanisms by which signals generated at the cell surface may be transduced.
As discussed below, the ability of the B cell to distinguish among regulatory species is
probably determined at multiple levels. These include differential receptor expression,
differential receptor coupling to specific second-messenger generating systems, and dif-
ferential cellular programming for specific responses to specific second messengers. At
the most primary level, receptors for regulatory factors may be differentially expressed
at specific stages of B cell proliferation or differentiation. For example, growth factor
receptors, e.g., IL2 receptors, are not expressed at detectable levels until cells reach
G,.' In the case of the lymphokine originally designated BCGF,, receptors are ob-
viously expressed on Go B cells since these cells respond to BCGF, by increasing in
surface Ia expression.* Although relative isotype distribution changes, cell surface im-
munoglobulin is apparently expressed throughout proliferation and differentiation un-
til the plasma cell stage is rea~hed.~
The utilization of varying biochemical coupling mechanisms to transduce signals
which are generated by binding of ligands to different receptors provides a second
mechanistic level at which differential responsiveness to regulatory species is generated.
For example, antigen-mIg-mediated signals are transduced via activation of polyphos-
phatidylinositol hydrolysis leading to intracellular free calcium mobilization and acti-
vation of a Ca++-a nd phospholipid-dependent protein kinase, protein kinase
However, signals generated as a result of BCGF, binding are transduced by an, as yet,
undefined mechanism which clearly does not involve activation of PI metabolism, cal-
cium mobilization, or membrane depolarization (see below).
Finally, in some instances, cells in different phenotypic or differentiative states re-
spond differently to the same second messenger, indicating that their phenotype may
include a certain inherent programming of responses to specific second messengers.
For example, while normal quiescent B cells respond to protein kinase C activators,
e.g., phorbol myristate acetate, by increased expression of Ia antigen, examination of
a series of B cell lymphomas revealed patterned responses involving up and down reg-
ulation of IgM, IgD, and DR expression following stimulation with phorbol diesters.14
These data suggest that lymphomas "frozen" in specific differentiative states respond
differently to activation of the protein kinase C second-messenger system. Differential
programming, presumably, also occurs in normal B cells undergoing an immune re-
sponse. For example, cells in G, might respond to generation of the same second mes-
senger differently than lymphoblasts.
It is clear that regulation of lymphocyte activation, proliferation, and differentiation
is complex and multifaceted, involving more than simply presence or absence of the
appropriate regulatory species. Appropriate receptors must be expressed, receptors
must be coupled to appropriate biochemical transduction mechanisms and the cells
must be programmed to respond appropriately to the transduced signal. It is the goal
of this report to review our current understanding of the transduction mechanisms
which may be operative during B cell activation. To this end we will first discuss mech-
anisms which are potentially operative and then review our recent findings regarding
signal transduction via mIg and receptors for BCGF,.
11. TRANSMEMBRANE SIGNALING MECHANISMS
Antigens, mitogens, and cytokines which regulate B lymphocyte physiology all ap-
pear to exercise their effects by interacting with cell surface receptor or acceptor mol-
ecules rather than by crossing the plasma membrane. The information or "signal"
generated by the interaction of ligand with receptor must be rapidly communicated to
the interior of the cell so the appropriate response can be made. This involves biochem-
ical transduction of the signal generating intracellular "second messengers". The con-
cept of a second messenger was originally proposed by Sutherland and Rall based upon
their studies of the effects of adrenaline on liverI5 and has been, subsequently, applied
to a wide variety of cell activation systems. The notion of a second messenger is espe-
cially attractive when applied to systems in which ligand receptor interactions lead to
rapid alterations in cell physiology. Rapid alterations in physiology such as membrane
depolarization by anti-Ig-stimulated B cells can occur only by modification of existing
enzymes and proteins, since they occur before detectable increases in RNA and protein
synthesis. Covalent modifications which might radically change the biologic activities
of substrates, such as phosphorylation, methylation, or adenylation, are the most
likely to be operative in these systems. Similarly, noncovalent modifications such as
proteolytic cleavage or protein-protein interactions which alter biologic activity may
also be important intermediary steps in signal transduction in some instances.
A. Protein Phosphorylation
Recently, much interest has been focused on the role of protein phosphorylation in
transmembrane signaling. A great diversity of cellular proteins may be influenced by
cycles of phosphorylation and dephosphorylation at serine, threonine, and tyrosine
residues. Most cellular phosphoproteins are serine phosphorylated, while succeedingly
less phosphorylation occurs at threonine and tyrosine residues, respectively. In fibro-
blasts about 90% of phosphoprotein is phosphoserine, 10% is phosphothreonine, and
0.002% is phosphotyrosine.16 Stimulation of cells with epidermal growth factor causes
a rapid tenfold increase in tyrosine phosphorylation." Similar rapid increases in tyro-
sine phosphorylation are induced in a variety of other tissues by other growth factors,
including platelet-derived growth factor, insulin, and somatomedin C.'' Cell surface
receptors for these factors have, in some cases, been shown to be protein kina~es,'~.~O
as have certain oncogenes including PP60 SRC.'' Other independent protein kinases
have been defined and are, in some instances, implicated in specific transduction sys-
tems. These kinases are themselves dependent on specific second messengers for their
activity. They include cyclic AMP (CAMP)-dependent protein kinase (protein kinase
A), cyclic GMP (&MP)-dependent protein kinase (protein kinase G), calmodulin-de-