Signal Transduction and the Coordination of B Lymphocyte Development and Function I: Transduction of BCR Signals from the Cell Membrane to the Nucleus

278 Pages·2000·7.776 MB·English

by  Louis B. Justement (auth.), Louis B. Justement Ph.D., Professor Katherine A. Siminovitch M.D. (eds.)

Current Topics in
Microbiology
and Immunology
245/1
Editors
R.W. Compans, Atlanta/Georgia
M. Cooper, Birmingham/Alabama
J.M. Hogle, Boston/Massachusetts· Y. Ito, Kyoto
H. Koprowski, Philadelphia/Pennsylvania· F. Melchers, Basel
M. Oldstone, La Jolla/California· S. Olsnes, Oslo
M. Potter, Bethesda/Maryland· H. Saedler, Cologne
P.K. Vogt, La Jolla/California· H. Wagner, Munich
Springer-Verlag Berlin Heidelberg GmbH
Signal Transduction
and the Coordination
of B Lymphocyte
Development and Function I
Transduction of BCR Signals
from the Cell Membrane to the Nucleus
Edited by L.B. Justement
and K.A. Siminovitch
With 22 Figures and 5Tables
Springer
LOUIS B. JUSTEMENT, Ph.D.
Associate Professor
Division of Developmental & Clinical Immunology
Department of Microbiology
University of Alabama at Birmingham
378 Wallace Tumor Institute
Birmingham, AL 35492-3300
USA
e-mail: [email protected]
Professor KATHERINE A. SIMINOVITCH, M.D.
Department of Medicine
University of Toronto
Mount Sinai Hospital
600 University Ave., Rm. 656A
Toronto, Ontario
CANADA M5G IX5
e-mail: [email protected]
Cover Illustration: Part 1 - Schematic representation of the major signaling pathways
activated in response to antigen-mediated cross-linking of the B cell antigen receptor
(BCR) complex. Aggregation of the BCR leads to activation of multiple protein tyrosine
complexes that inducibly phosphorylate multiple intracellular e!fector proteins. Tyrosine
phosphorylation of adaptor proteins promotes the formation of multimolecular complexes,
which facilitate the activation and/or localization "/. key signaling proteins. Transcription
factor activation is ultimately controlled by Ca + ·dependent (calcineurin and Ca2+.
calmodulin kinase) as well as calcium independent pathways (Ras and RaeI). Differential
transcription factor activation determines the nature of the B cell biological response.
Cover Design: design & production GmbH, Heidelberg
ISSN 0070-217X
ISBN 978-3-642-63017-0 ISBN 978-3-642-57066-7 (eBook)
DOI 10.1007/978-3-642-57066-7
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Originally published by Springer-Verlag Berlin Heidelberg New York in 2000
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Preface
Proper development and differentiation of B lymphocytes is es
sential to ensure that an organism has the ability to mount an
effective humoral immune response against foreign antigens. The
immune system must maintain a balance between the deletion of
harmful self-reactive Bcells and the generation ofa diverse rep
ertoire of Bcells that has the ability to recognize an almost un
limited array offoreign antigens. The need to delete self-reactive
cells is tempered by the need to avoid the generation of large
functional holes in the repertoire of foreign antigen-specific B
cells that patrol the periphery. To accomplish this, the immune
system must reach a compromise by eliminating only the most
dangerous autoreactive clones, while allowing less harmful au
toreactive Bcells to exist in the periphery where they may com
plement the organism's ability to mounta rapid response against
invadingmicro-organisms. Those autoreactivecells that do enter
the peripheral pool are subject to a number of conditional re
straints that effectively attenuate their ability to respond to self
antigens. Deleterious alterations in the homeostasis between
toleranceinductionand recruitment ofBcells into the functional
repertoire may lead to increased susceptibility to autoimmune
disease or infection, respectively. Therefore, delineation of the
molecular processes that maintain immunological homeostasis in
the Bcell compartment is critical.
The balance between tolerance and immunity can be altered
byfactors thatareextrinsicaswellasintrinsictotheBcellleading
either to anergization and elimination, or to activation and dif
ferentiation intoantibody-secretingplasmacellsormemorycells.
Extrinsic factors that regulate the balance between tolerance and
immunityincludedifferencesin the amount,avidityand timingof
antigen presentation, and the expression of molecules by other
immunecellsortissuesthatplayaroleinelimination,retentionor
expansion of B cells. Equally important is the regulation of the
intrinsicsignalingthreshold thatis required to triggeran antigen
specific B cell clone and which determines whether that cell
undergoes tolerance induction versus activation in response to a
VI Preface
given antigenic challenge. Regulation of signaling thresholds in
individual Bcell clonesisaffected byalterations in the expression
or function of molecules that adjust the strength of the signal
delivered via the BCR. Triggering thresholds can be determined
by inherited genetic polymorphisms that affect the expression or
activity ofspecific intracellular effector proteins, or they can be
altered within an individual B cell clone by previous encounters
with antigen that lead to anergization or memory cell formation.
Significant progress has been made towards delineation of
the intrinsic molecular processes that regulate B lymphocyte
immune function. Recent observations have provided a clearer
picture of the interactive signaling pathways that emanate from
the mature B cell antigen receptor (BCR) complex and the dif
ferent precursor complexes that are expressed during develop
ment. Studies have also revealed that the net functional response
to a given antigenic challenge is affected by the combined action
of BCR-dependent signaling pathways, as well as those origi
nating from various coreceptors expressed by Bcells. The chap
tersin this volumeprovideasummaryofcurrentfindings relating
to the molecular control of B cell development and differentia
tion. Because it is virtually impossible to include a discussion of
every aspect related to signal transduction in B lymphocytes, an
effort has been made to focus on signaling through the BCR
complex and co-receptors that regulate BCR-dependent signal
ing. Part I of the volume deals with the biochemical/molecular
aspects of BCR-dependent signal transduction beginning with
membrane proximal events and culminating with regulation of
genetranscriptionin thenucleus. Part Ialsocoversthemolecular
function ofspecificcoreceptors thatare involved in regulation of
BCR signaling.
It is now well established that reversible tyrosine phosphor
ylation plays an important role in regulating B cell biology. In
particular, bindingofantigen tothe BCRpromotestheactivation
of several protein tyrosine kinases (PTK) that, in conjunction
with protein tyrosine phosphatases (PTP), alter the homeostasis
of reversible tyrosine phosphorylation in the resting Bcell. The
net effect is a transient increase in protein tyrosine phosphory
lation that facilitates the phosphotyrosine-dependent formation
of effector protein complexes, promotes targeting of effector
proteins to specific microenvironments within the B cell and
initiates the catalytic activation ofdownstream effector proteins.
The role of protein tyrosine kinases and phosphatases in initia
tion and propagation ofsignal transduction via the BCR is dis
cussedinthefirstchapter. InitiationofBlymphocyteactivationis
dependent on the tyrosine phosphorylation-dependentformation
Preface VII
of multi-molecular effector protein complexes that activate
downstream signaling pathways. The formation of such com
plexes was initially hypothesized to occur primarily via effector
protein binding to the BCR complex itself. However, recent
studies havedemonstrated that productive signalingvia the BCR
is, in fact, dependenton tyrosinephosphorylation ofoneormore
adapter proteins that playa crucial role in recruitment and or
ganization of effector proteins at the plasma membrane. The
second chapter provides a discussion of the SLP65/BLNK
adapter protein and its role in recruitment and activation ofkey
signal transducing effector proteins in the Bcell. After the BCR
hasbeenengaged byantigenand theactivation responsehasbeen
initiated, numerous second messengers and intermediate signal
transducing proteins are activated. These include the production
oflipid second messengers by phosphatidylinositol 3-kinase, the
hydrolysis of phosphatidylinositol 4,5-bisphosphate to yield di
acylglyceroland 1,4,5-inositoltrisphosphate,and themobilization
ofCa2+. Numerous intermediate signaling proteins are also ac
tivated, including the Ras and RapI GTPases, aswell as the Erk,
JNK and p38 MAP kinases. The third chapter provides a dis
cussion of the current understanding of how these second mes
sengers and intermediate signaling proteins function in a
concerted manner to regulate transcription factor activation and
gene transcription in the Bcell. In the fourth chapter the role of
the cytoskeletal apparatus in B cell activation is discussed.
Studies from numerouscell systemsindicate that the cytoskeletal
apparatus not only provides structural integrity for a cell, but it
also provides a cell with the capacity to compartmentalize and
redistribute proteins in a dynamic manner in order to modulate
signal transduction and, thus, cellular function. It is now be
coming clear that the cytoskeletal apparatus plays an important
role in B cell activation through its physical/functional interac
tionswithsignal transducingeffectorproteins. Finally, the ability
of B lymphocytes to respond to antigen is regulated by the ex
pression of specific genes that play a role in the activation re
sponse. The fifth chapter presents a discussion on Pax-5/BSAP,
which is a DNA-binding protein that plays a pivotal role in
controlling theexpression ofgenes thatare required for the Bcell
response to antigen. A number of potential targets for Pax-5f
BSAP have been identified that are directly associated with the
BCR, or with signal transduction in B cells. The current under
standing ofhow Pax-5/BSAPfunction is regulated and its role in
gene transcription is covered there.
Itis nowclear thatsignal transduction through the BCRcan
be modulated by a number ofcoreceptors, in effect to maximize
VIII Preface
theimmuneresponsewhenthe Bcellencountersaforeign antigen
in the appropriate microenvironment, to attenuate the response
in instances where the Bcell response to a self-antigen might be
detrimental to the host and, finally, to modulate Bcell activation
under conditions in which an adequate immune response has
already been made. In general, it is apparent that B cell core
ceptors function as docking structures that recruit specific effec
torproteins in a phosphotyrosine-dependentmanner. Depending
ofthe context in which a Bcell encounters antigen, one or more
coreceptors can be engaged and, based on their ability to recruit
selected effector proteins, either enhance or attenuate signaling
through the BCR complex. The final two chapters of Part I
provide an overview of the CDI9, CD22 and FcyRIIb corecep
tors describing their molecular function as well as their role in
regulation ofBCR-dependent signal transduction and Bcell im
mune function.
In Part 2 of this volume the role of BCR- and accessory
molecule-dependent signal transduction in regulation of specific
physiological processes associated with B cell development and
differentiation will be covered. The BCR complex performs an
essential function during Bcell development and differentiation.
In pro-B and pre-B cells, expression ofthe membrane immuno
globulin heavy chain of the BCR in conjunction with pseudo
light chain gene products is essential for establishing allelic
exclusionandfor regulationoforderedgene recombinationat the
heavy and light chain loci. Subsequent expression of a mature
BCRcomplexon thesurfaceofimmature Bcellsis importantfor
tolerance induction and selection into the peripheral Bcell pool.
Duringtheprocessoftoleranceinduction, bindingofself-antigen
to the BCRon Bcellscanlead to anergization,clonalelimination
or receptor editing, depending on the qualitative/quantitative
nature ofthe signal delivered and the developmental state ofthe
Bcell. Finally, once Bcells have been selected and migrate to the
periphery, the BCR complex mediates antigen-dependent acti
vation and selection into the memory B cell pool. In the first
chapter ofPart 2, the discussion focuses on the well-documented
differences in the response ofimmature and mature stage Bcells
to antigen. Based oncurrent informationit remainscontroversial
as to whether the differential response of these populations re
flects processes that are intrinsic to B cells at specific stages of
development or, rather, reflect extrinsic processes that determine
the functional outcome of antigen-dependent signaling in im
mature versus mature Bcells. In this context, the molecular and
cellular characteristics ofimmature Bcells are discussed and an
evaluation of whether they support a role for intrinsic versus
Preface IX
extrinsic factors in regulating the outcome of BCR signaling
presented.
Before the mature BCR complex is expressed on the surface
of the B cell, the gene elements that encode the heavy and light
chain polypeptides that comprise the receptor must be success
fully recombined in a process termed V(O)J recombination. This
recombination process is highly regulated during development
with respect to the expression of recombinase activity and the
susceptibility ofspecific loci to undergo rearrangement. The high
degree of control imposed on V(O)J recombination, which is
crucial for successful enforcement of allelic exclusion and for
maintenance ofthe fidelity ofrearrangement,isexerted atseveral
levels including: (I) transcription of recombinase genes; (2) ac
cumulation ofrecombinase gene products; and (3) accesibility of
specific loci to recombinase activity. The second chapter sum
marizes whatiscurrently known about the signalingpathwaysin
the Bcell that underlieeach ofthe regulatory mechanismsabove.
Because V(O)J recombination is an error-prone process in terms
of the actual joining of gene elements, it is subject to quality
control at many levels, inherently allowing for multiple attempts
at rearrangement and correction of the final recombined gene
product. Additionally, immune tolerance to self-antigen can be
established in emerging B cells by reactivating the capability to
undergo Y(O)J recombination. Alternatively, self-tolerance can
beeffectively imposed by triggering Bcells to undergo apoptosis.
The third chapter focuses on what is currently known about the
ability of the BCR to mediate both enhancing and suppressing
effects on B cell development, Y(O)J recombination and apop
tosis.
Once B cells have encountered foreign antigen in the ap
propriate peripheral microenvironment, numerous soluble and
cell-associated factors playa crucial role in driving proliferation
and differentiation of the antigen-stimulated cell. The fourth
chapter discusses current knowledge pertaining to signal trans
duction through C040, which has been shown to playa critical
role in regulating B cell growth and differentiation, class
switching, germinal center formation and the generation of
memory cells. Once B cells have encountered antigen and have
received additional signals through C040, they mature as anti
gen-presenting cells resulting from the upregulation of C023,
B7.1, B7.2 ICAMI and C044. In the fifth chapter evidence is
presented indicating that the antigen-processing function of B
cells is regulated both developmentally and in response to an
arrayofstimulithatarereceived bythe Bcellthroughcellsurface
signaling molecules, including the BCR, the C021/COI9 com-
X Preface
plex, MHC class II, CD40 and FcyRllb. Finally, as the B cell
response to antigen progresses, it is accompanied by class
switching in which the isotype of antibody being synthesized is
changed. This process does not affect the inherent specificity for
antigen, but it does alter the effector function of the antibody
produced. Classswitchinghasbeenshownto occurinresponse to
signals delivered to the Bcell through cytokine receptors, CD40
and the BCR complex itself. The sixth chapter discusses what is
currently known about the specificity of isotype switch recom
bination with regard to the regulation ofgermline transcripts by
signals delivered through cell surface receptors.
The topics covered in this two-part volume are intended to
provide information on the biochemical/molecular aspects of
signal transduction through the BCR and to relate the mecha
nistic processes associated with signal transduction in B cells to
immunologicallyrelevantfunctional outcomes. Itisalso intended
as a general overview of the molecular processes that underlie
Bcell developmentand differentiationand hopefully will serve as
a reference for those who wish to delve further in to the issues
discussed herein or related topics.
L.B. JUSTEMENT
K.A. SIMINOVITCH