Table Of ContentCurrent Topics in
Microbiology
and Immunology
184
Editors
A. Capron, Lille . R.W. Compans, Atlanta/Georgia
M. Cooper, Birmingham/Alabama' H. Koprowski,
Philadelphia . I. McConnell, Edinburgh . F. Melchers, Basel
M. Oldstone, La Jolla/California . S. Olsnes, Oslo
M. Potter, Bethesda/Maryland . H. Saedler, Cologne
P. K. Vog!, Los Angeles' H. Wagner, Munich
I. Wilson, La Jolla/California
Adhesion in
Leukocyte Homing
and Differentiation
Edited by D. Dunon, C. R. Mackay
and B.A. Imhof
With 37 Figures and 13 Tables
Springer-Verlag
Berlin Heidelberg New York
London Paris Tokyo
Hong Kong Barcelona
Budapest
DOMINIQUE DUNON, Ph.D.
CHARLES R. MACKAY, Ph.D.
BEAT A. IMHOF, Ph.D.
Basel Institute for Immunology
Grenzacherstr. 487
4005 Basel
Switzerland
Cover illustration: Colonization of different organs (large
spheres) by leukocytes (small spheres) is mediated by
adhesion molecules. Leukocyte subsets can also undergo
differentiation which is indicated by the colour changing
to red. (Designed by Andre Traunecker, Basel Institute for
Immunology.)
Cover design: Harald Lopka, Jlvesheim
ISSN 0070-217X
ISBN-13:978-3-642-78255-8 e-ISBN-13:978-3-642-78253-4
001: 10.1007/978-3-642-78253-4
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Preface
This volume of Current Topics in Microbiology and
Immunology was planned in parallel with an EM BO
workshop on cell-cell Interactions in Leukocyte Homing
and Differentiation held at the Basel Institute for
Immunology in November 1992, and many of the workshop
speakers have contributed to it.
Cell adhesion is one of the most dynamic fields of
biological research and presented in this book is the current
knowledge on the structure and function of the major
families of cell adhesion molecules-the integrins, the
selectins, the immunoglobulin superfamily, and CD44.
Complex interactions between the members of these
families mediate diverse adhesion functions, including
leukocyte-leukocyte interactions, lymphocyte homing,
inflammation, and lymphocyte-stromal cell interaction
during hematopoiesis. A great deal of emphasis is placed
on the regulatory elements that control the expression and
function of adhesion molecules. Cytokines not only induce
the expression of certain adhesion molecules, but may also
modify their functional status. For instance, the integrins
exist in either an inactive nonfunctional form or an active
functional form, and a number of intracellular or extracellular
stimuli modify integrin function. This is particularly
important during leukocyte binding to endothelium and
transendothelial migration, which proceeds through a
cascade of adhesion events. Although cell adhesion
molecules play an important role in many processes, this
book concentrates on their role within the immune system.
A number of chapters discuss the migration of lymphocytes
between hematopoietic organs such as the thymus, lymph
nodes, Peyer's patches, and spleen. Other chapters discuss
the changes in leukocyte migration during an inflammatory
response. The underlying theme in all of these chapters is
the regulation and function of cell adhesion molecules.
VI Preface
In brief, this book introduces new aspects of cell
adhesion on the molecular and biological level. The tables
in the appendix should be especially helpful for newcomers
to the field.
DOMINIQUE DUNON
CHARLES R. MACKAY
BEAT A. IMHOF
Contents
The Dominance of Antigen-Specific Receptors
in Antigen-Specific Immune Responses
F. MELCHERS ................................. 1
I Adhesion Molecules
Integrins and Their Ligands
A. SONNENBERG. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Platelet Endothelial Cell Adhesion Molecule (CD31)
H.M. DELISSER, P.J. NEWMAN, and S.M. ALBELDA 37
CD44: A Multitude of Isoforms
with Diverse Functions
U. GONTHERT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
The Selectins and Their Ligands
D. VESTWEBER ................................ 65
II Regulation of Leukocyte-Endothelial
Cell Adhesion
A Model of Leukocyte Adhesion
to Vascular Endothelium
N. HOGG ..................................... 79
Regulation of Adhesion Receptor Expression
in Endothelial Cells
P. DEFILIPPI, L. SILENGO, and G. TARONE ......... 87
Regulation of Leukocyte Recruitment
by Proadhesive Cytokines Immobilized on Endothelial
Proteog Iyca n
Y. TANAKA, D.H. ADAMS, and S. SHAW. . . . . . . . . . . . 99
'" Lymphoid Cell Homing Mechanisms
Migration of Activated Lymphocytes
A. HAMANN and S. REBSTOCK ................... 109
VIII Contents
The Peyer's Patch Homing Receptor
M.C.-T. Hu, B. HOLZMANN, D.T. CROWE,
H. NEUHAUS, and I. L. WEISSMAN ................ 125
Pro-T Cell Homing to the Thymus
D. DUNON, P. RUIZ, and BA IMHOF. . . . . . . . . . . . .. 139
Quantitative Analysis of Lymphocyte Fluxes
In Vivo
R. PABST, R. M. BINNS, H. J. ROTH KOTTER,
and J. WESTERMANN. . . . . . . . . . . . . . . . . . . . . . . . . .. 151
Lymphocyte Recirculation and Life Span
In Vivo
A.J. YOUNG, J.B. HAY, and C.R. MACKAY 161
IV Leukocyte Homing to Inflamed Tissues
The Contributions of Integrins to Leukocyte
Infiltration in Inflamed Tissues
T.B. ISSEKUTZ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 177
Regulation of Adhesion and Adhesion Molecules
in Endothelium by Transforming Growth Factor-fJ
Y. KHEW-GOODALL, J.R. GAMBLE, and MA VADAS 187
Transendothelial Migration
C.W. SMITH .................................. 201
V Adhesion Molecules in Differentiation
and Activation of Lymphocytes
CD44 and Other Cell Interaction Molecules
Contributing to B Lymphopoiesis
P. W. KINCADE, Q. HE, K. ISHIHARA, K. MIYAKE,
J. LESLEY, and R. HYMAN. . . . . . . . . . . . . . . . . . . . . .. 215
CD4, CD8, and CD2 in T Cell Adhesion and Signaling
T.L. COLLINS, W.C. HAHN, B.E. BIERER,
and S.J. BURAKOFF . . . . . . . . . . . . . . . . . . . . . . . . . . .. 223
Activation and Inactivation of Adhesion Molecules
Y. VAN KOOYK and C.G. FIGDOR ....... . . . . . . . . . . 235
Appendix. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 249
Subject Index ................................ 257
Contributors
(Their addresses can be found at the beginning of their
respective chapters.)
ADAMS D.H. ...... 99 KHEW-GOODALL Y. 187
ALBELDA S.M. ..... 37 KINCADE P.W. . . . . .. 215
BIERER B.E. ....... 223 LESLEY J. . . . . . . . . .. 215
BINNS R.M. ....... 151
MACKAY C.R ....... 161
BURAKOFF S.J. .... 223
MIYAKE K .......... 215
COLLINS T.L. ...... 223
NEUHAUS H. ....... 125
CROWE D.T. . . . . . .. 125 NEWMAN P.J. ...... 37
DeFILIPPI P. . . . . . . . 87 PABST R ........... 151
DelisSER H.M. .... 37
DUNON D. ........ 139 REBSTOCK S. .. . . . .. 109
ROTH KOTTER H.J. ... 151
FIGDOR C.G. ...... 235 RUlz P ............ 139
GAMBLE J.R. ...... 187 SHAW S. .......... 99
GONTHERT U. . . . . . . 47 SI LENGO L. ........ 87
SMITH C.W. . . . . . . .. 201
HAHN W.C. ....... 223
SONNENBERG A .... 7
HAMANN A ....... 109
HAY J.B. ......... 161 TANAKA Y. ......... 99
HEQ. ............ 215 TARONE G. ........ 87
HOGG N. ......... 79
VADAS MA . . . . . .. 187
HOLZMANN B. ..... 125
VAN KOOYK Y. ..... 235
Hu M.C.-T. ....... 125
VESTWEBER D. ..... 65
HYMAN R. ........ 215
WEISSMAN I,L. ..... 125
IMHOF BA ....... 139
WESTERMANN J. .... 151
ISHIHARA K. ....... 215
ISSEKUTZ T.B. . . . . .. 177 YOUNG AJ. . . . . . . .. 161
The Dominance of Antigen-Specific
Receptors in Antigen-Specific
Immune Responses*
F. MELCHERS
The theme of my keynote address (which, according to the Oxford American
Dictionary, is "a speech, especially at a political convention, stating basic
policies and principles") is simple: I would like to emphasize the dominant
role that antigen-specific receptors play in the responses of lymphocytes.
Over 20 years ago, when the Basel Institute for Immunology was
founded, the theory of clonal selection had long been postulated, whereby
antigens selected preexisting lymphocytes with antigen-specific receptors
to antigen-specific responses. This dominance of antigen in selecting a
resting lymphocyte to enter the cell cycle and differentiate to effector
functions led some researchers to think that antigen was all that was needed
to stimulate an immune response. It had, however, just been recognized
that three types of cells-B lymphocytes, T lymphocytes and accessory (A)
cells-had to cooperate in an immune response to an antigen, so that B
cells would proliferate and produce and secrete specific antibodies. This
indicated that binding of antigen to an antigen-specific receptor on a
lymphocyte alone was insufficient to stimulate proliferation and differen
tiation of lymphocytes.
A few years later, it became clear that the cooperation of T cells on the
one hand and A or B cells on the other was guided by MHC molecules.
We now know that antigen-specific receptors on T cells recognize processed
antigen in the form of peptides bound to MHC molecules on A or B cells.
T cells learn this "MHC-restricted" recognition in the thymus where they
are formed from precursors. The antigen-specific recognition leads to the
production of antigen-unspecific cytokines which stimulate the proliferation
and differentiation of antigen-activated cells.
"This was the keynote address given at the EMBO Workshop on "Cell-Cell Ineractions in
Leukocyte Homing and Differentiation held at the Basel Institute for Immunology in November
1992 and organized by Beat Imhof, Charles Mackay, Ton Rolink, Dominique Dunon and Ursula
Gunthert.
Basel Institute for Immunology, Grenzacherstrasse 487,4005 Basel, Switzerland
2 F. Melchers
At the same time, mitogens such as agglutinins, polyanions and
lipopolysaccharides were found to be polyclonal activators of lymphocytes,
again suggesting that binding of antigen to antigen-specific receptors was
not the only thing needed-in these cases not even needed at all-to
stimulate lymphocytes to respond.
Although the cooperation of three types of cells immediately suggested
intimate contacts between them, research in the following years con
centrated on the soluble cytokines and their receptors in order to clarify
the regulation of immune responses. Only recently have molecular forms of
cell-cell contacts been identified as essential elements in: (1) the migration
of cells into the areas where they respond, (2) the adhesion of cells to each
other and (3) the signaling of these cells with the aim of beginning
perpetuating and even ending their responses. I am grateful that so many
eminent scientists working on cell adhesion and migration have come to
Basel to make this workshop an exciting event.
Since the old days, when binding of antigens to their specific re
ceptors on lymphocytes was expected to be the dominant, if not the only,
thing that mattered, the pendulum has swung almost to the opposite
extreme: antigen-independent cell-cell contacts and the binding of
soluble antigen-unspecific cytokines to their polyclonally distributed
receptors are thought tobe the most important elements of lymphocyte
interactions.
This may well be true for cell migrations and cell adhesions. However,
if the concept of clonal selection is to be upheld, cell-cell contacts and
interactions of soluble cytokines with their receptors must be dominated by
the state of antigen-specific receptors on T and B cells. T cell receptors and
immunoglobulin molecules should control proliferation and subsequent
differentiation to effector functions. Ia m curious to know how lymphocytes
organize all these molecules involved in contact and responses so that T
cell receptors and immunoglobulin molecules on the surface tell the rest of
them whether to initiate reactions that lead to entry
into the cell cycle and into differentiation or not. I
am even more curious to know whether immuno
globulin-like molecules with surrogate light chains
on pre-B cells already display this dominant role in
the control of lymphocyte development.
This workshop on "Cell- Cell Interactions in
Leukocyte Homing and Differentiation" was planned
with Alan Williams as an active participant. Sadly,
Alan died of cancer in April 1992 at the age of 47.
His scientific interest the structure and evolution of
the immunoglobulin domain, was and remains of
prime interest for a meeting on cell adhesion in the
ALAN WILLIAMS immune system. The immunoglobulin domain, in its
