Table Of ContentLYMPHOCYTE ACTIVATION
AND IMMUNE REGULATION IX
ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
Editorial Board:
NATHAN BACK, State University of New York at Buffalo
IRUN R. COHEN, The Weizniann Institute of Science
DAVID KRITCHEVSKY, Wistar Institute
ABEL LAJTHA, N. S Kline Institute for Psychiatric Research
RODOLFO PAOLETTI, University of Milan
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Volume 512
LYMPHOCYTE ACTIVATION AND IMMUNE REGULATION IX: Homeostasis and
Lymphocyte Traffic
Edited by Sudhir Gupta, Eugene Butcher, and William Paul
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LYMPHOCYTE ACTIVATION
AND IMMUNE REGULATION IX
Homeostasis and Lymphocyte Traffic
Edited by
Sudhir Gupta
University of California, Irvine
Irvine, California
Eugene Butcher
Stanford University School of Medicine
Stanford, California
and
William Paul
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, Maryland
Springer Science+Business Media, LLC
Library of Congress Cataloging-in-Publication Data
International Conference on Lymphocyte Activation and Immune Regulation (9th: 2002
Newport Beach, Calif.)
Lymphocyte activation and immune regulation IX: homeostasis and lymphocyte traffic
/edited by Sudhir Gupta, Eugene Butcher, and William Paul.
p. cm. — (Advances in experimental medicine and biology; v. 512)
"Proceedings of the Ninth International Conference on Lymphocyte Activation &
Immune Regulation held in Newport Beach, California on February 8-12, 2002."
Includes bibliographical references and index.
ISBN 978-1-4613-5226-6 ISBN 978-1-4615-0757-4 (eBook)
DOI 10.1007/978-1-4615-0757-4
1. Lymphocyte transformation—Congresses. 2. Immune
response—Regulation—Congresses. 3. Cells—Motility—Congresses. I. Gupta, Sudhir. II.
Butcher, Eugene. III. Paul, William E. IV. Title. V. Series.
QR185.8.L9 1553 2002
616.07'9—dc21
2002027574
Proceedings of the 9th International Conference on Lymphocyte Activation and Immune Regulation held in
Newport Beach, California on February 8-10, 2002.
ISBN 978-1-4613-5226-6
©2002 Springer Science+Business Media New York
Originally published by Kluwer Academic Publishers in 2002
Softcover reprint of the hardcover 1st edition 2002
10 9 8 7 6 5 4 3 21
A C.I.P. record for this book is available from the Library of Congress
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No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any
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PREFACE
During the past 5 years major progress has been made in the understanding the
basic mechanisms oflymphocyte homeostasis and in the developmental relationship
between different memory T subsets and their traffic patterns and functional
significance. This volume highlights the currentconcepts oflymphocyte development,
factors regulating lymphocyte trafficking and development, and specialized
characteristicsandfunctional propertiesofnaiveandmemorysubsets.
Thisvolume is divided into3sections. SectionIdeals with factors that regulate the
development and maturation of T cells and B cells and lymphocyte traffic. The
significanceofC-kit,Bcl-6,IL-7andVavinthedevelopmentofTandBlymphocytes
is discussed. A role of lymphotoxins and VAP-I in trafficking of leucocytes is
reviewed. Finally, the trafficking and homing characteristics of T cell and B cell
subsets, and the regulation of these processes during the immune response, is
presented.
Section II discusses various aspects ofnaive and memory Tcell biology, including
clonal expansion, reprogramming of genes including those encoding cytokines and
cytotoxic granules, changes in the expressionofcell surface proteins involved incell
cell adhesion, homingofnaiveandmemoryTcells,the role ofMHC and cytokines in
the maintenance of naive and memory T cells, and the characterization and
differentiationofvirus-specificmemoryTcellheterogeneityinmiceandhumans.
Novelmethodsofvisualizationofimmunecellsandimmunesynapses are reviewed
in Section III. This includes tracking of dendritic cells in vivo, monitoring arterial
smooth muscle-specific T cells in the inflamed vasculature, imaging of molecular
migrations in immune synapses, and visualization ofvarious immune cells in intact
lymphoidtissuesbytwophotonconfocalimaging.
This volume should be of interest to immunologists, molecular biologists,
microbiologists, pathologists, academic physicians, cell biologists, and scientists and
cliniciansinterestedinvaccinedevelopment.
SudhirGupta
EugeneButcher
WilliamPaul
v
CONTENTS
LYMPHOCYTEDEVELOPMENTANDLYMPHOCYTETRAFFIC
1.LYMPHOCYTEDEVELOPMENTINNEONATALANDADULT
C-KIT-DEFICIENT(C_KITwlW) MICE......................................................... I
ClaudiaWaskowandHans-ReimerRodewald
2.DEVELOPMENTOFANTIGEN-SPECIFICHELPERT CELL
RESPONSESINVIVO: ANTIGEN-SPECIFICTHCELLSUBSETS..... II
LouiseMcHeyzer-Williams,LaurentMalherbe,MichaelEisenbraun,
DavidDriver,andMichaelMcHeyzer-Williams
3.BCL-6UNCOUPLESBLYMPHOCYTEPROLIFERATIONFROM
DIFFERENTIATION 21
DouglasT. Fearon,PeterM. Manders,andSimonD.Wagner
4.THEROLE OFVAVPROTEINSINBCELLRESPONSES 29
MartinTurner
5.TRAFFICPATTERNSOFBCELLSANDPLASMACELLS 35
JasonG. Cyster,K. MarkAnsel,VuN.Ngo,DianaC. Hargreaves,and
TheresaT. Lu
6.LYMPHOCYTETRAFFICEINLYMPHOIDORGANNEOGENESIS
DIFFERENTIALROLESOFLTaANDLTaIL 43
DanielleL. Drayton,KeeChan,WernerLesslauer,JasonLee,XiaoYanYing,
andNancyH. Ruddle
7.REGULATIONOFSPLEENWHITE PULPSTRUCTUREAND
FUNCTIONBYLYMPHOTOXIN 49
DavidD. Chaplin
8.ENZYMATICCONTROLOFLEUKOCYTETRAFICKING: ROLEOF
VAP-I 57
MarkoSalmiandSirpaJalkanen
vII
viII CONTENTS
9.HOMESTATICCHEMOKINESANDTHETARGETINGOF
REGIONALIMMUNITY 65
EricJ. KunkelandEugeneC.Butcher
NAivE ANDMEMORYT CELLS
10.FACTORSREGULATINGNAiVET CELLSHOMEOSTASIS 73
CharlesD. Surh,JoyceTan,WilliamC. Kieper,andBettinaErnst
11.IL-7,THETHYMUS,ANDNAivET CELLS 81
YukariOkamoto,DanielC. Douek,RichardD.McFarland,and
RichardA. Koup
12.NEONATESSUPPORT"HOMEOSTATIC"PROLIFERATION 91
BookiMin,GregoryD. Sempowski,andWilliamE. Paul
13.SELF-RECOGNITIONANDTHEREGULATIONOFCD4+TCELL
SURVIVAL 97
RonaldN. Germain,IrenaStefanova,andJeffreyDorfman
14.TCR-INDEPENDENTPROLIFERATIONANDDIFFERENTIATION
OFHUMANCD4+CELLSUBSETSINDUCEDBYCYTOKINES....... 107
JensGeginat,StefaniaCampagnaro,FedericaSallusto,and
AntonioLanzavecchia
15.REGULATIONOFMEMORYCD4T CELLS:GENERATION,
LOCALIZATIONANDPERSISTENCE 113
SusanL. Swain,JavedN. Agrewala,DeborahM. Brown,andEulogiaRoman
16.SOMEPROPERTIESOFTCELLSINANIMALS 121
AngelaRicodeSouza,BradleySwanson,JenniferRobertson,JeremyBender,
JohnKappler,andPhilippaMarrack
17.GENERATIONANDCHARACTERIZATIONOFMEMORYCD4T
CELLS 129
S. Z.Ben-Sasson,IrenaZukovsky,AlizaBiton,RonVogel,GillesFoucras,
Nobuki Hayashi,andWilliamE. Paul
18.T CELLPROLIFERATION,DIFFERENTIATION,AND
RESTORATIONINLYMPHOPENICINDIVIDUALS:
FORCONTRIBUTEDVOLUMES 135
JianzhuChen,QingGe,BryanCho,andHermanN. Eisen
19.MIGRATIONOFPRIMARYANDMEMORYCD8T CELLS 141
LeoLefran~ois,AmandaL. Marzo,DavidMasopust,KimberlyS. Schluns,and
VaivaVezys
CONTENTS Ix
20.CYTOKINESANDMEMORY-PHENOTYPECDS+CELLS 147
JonathanSprent,AdamD.Judge,andXiaohongZhang
21.ANTMRALMEMORYT CELLRESPONSES: CORRELATIONWITH
PROTECTIVEIMMUNITYANDIMPLICATIONFORVACCINE
DEVELOPMENT 155
AlexandreHarari,KimEllefsen,PatrickChampagne,MassimoNobile,and
GiuseppePantaleo
22.HOMEOSTATICPROLIFERATIONBUTNOTTHEGENERATION
OFVIRUSSPECIFICMEMORYCDST CELLSISIMPAIREDIN
THEABSENCEOFIL-15ORIL-15Ra 165
E. JohnWherry,ToddC.Becker,DavidBoone,Murali-KrishnaKaja,
Averil Ma,andRafiAhmed
TRACKINGIMMUNECELLS
23.IRREVERSIBLEMARKINGOFDENDRITICCELLSINVIVO:
FORCONTRIBUTEDVOLUMES 177
SanjayGarg,AlpOran,CharlesMaris,andJoshyJacob
24.TRACKINGARTERIALSMOOTHMUSCLESPECIFICT CELLSIN
THEINFLAMEDVASCULATURE 183
BurkhardLudewig
25. REGULATIONOFT CELLMIGRATIONTHROUGHFORMATION
OFIMMUNOLOGICALSYNAPSES: THESTOPSIGNAL
HYPOTHESIS 191
MichaelL. Dustin
26.TWO-PHOTONIMAGINGININTACTLYMPHOIDTISSUE 203
SindyH. Wei,Mark1.Miller,MichaelD. CahalanandIanParker
INDEX 209
LYMPHOCYTE DEVELOPMENT IN NEONATAL AND
ww
ADULT C-KIT-DEFICIENT (C-KIT / ) MICE
Claudia Waskowand Hans-ReimerRodewald·
ABSTRACT
Hematopoieticstemcellsand lymphocyteprogenitorsexpress the receptor tyrosine
kinase c-Kit. In fetal and neonatal life, c-Kit plays a redundant role in T, and no
apparantrole in Bcell development. In neonatal mice deficient for both c-Kit and the
common ychain (ye), a component ofthe interleukin-7 (IL-7) receptor, the thymus is
alymphoid,andthereforelacksT cell receptor (TCR) 13,y, and 0 rearrangements. Thus,
a critical role for c-Kit in T cell development around birth is well established. More
recently, it has become possible to examine the impact of c-Kit deficiency under
conditions ofsteady state lymphopoiesis in adult life. Such analysis has been made
possible by the identification of a viable adult c-Kit-deficient (c-KitW/W) variant,
termedthe Vickidmouse. TheVickidmousearosebyoutcrossingc-KitW-bearing mice
ofthe WB strain, in which lack ofc-Kit is lethal, to a mixed genetic background. In
adult Vickid mice, mainstream al3 TCR+ thymocyte development, and B cell
development in the bone marrow are severely c-Kit-dependent with progressive age.
Analysis ofother pathways of developing T cells, i.e. CD4-CDS- (double neagative
[DN]) al3 TCR+and DN yo TCR+ thymocytes revealed that the development ofboth
lineages is also severely affected by lack ofc-Kit. However, numbers ofyo TCR+ T
cells decline beforenumbersofal3 TCR+Tcells in thethymus. Incontrast to T and B
celldevelopment,generationofNKcells isnotaffectedinadultc-KitW/Wmice.
INTRODUCTION
The receptor tyrosine kinase c-Kit is a growth factor receptor important for the
development and function of stem and progenitor cells. C-Kit is expressed in
•Dept. forImmunology,UniversityofUlm,0-89070Vim,Germany,[email protected],
[email protected],tel: 49-731-50023360,fax: 49-731-50023367
2 C.WASKOWANDH.-R.RODEWALD
hematopoietic cells, germ cells, melanocytes, intestinal pacemaker cells, and neuronal
cells(Bernstein et al., 1990; Besmer, 1991). According to this expression pattern, c
Kitdeficiency causes anemia, sterility, depigmentation (dominant white spotting), and
intestinal pacemakerdysfunction. Numerous naturallyoccurringc-Kit(Walleles)or Kit
ligand(Kitl; formerly termedstem cell factor [SCF], ormast cell growth factor (MGF])
(steel [SI] alleles) mutants have been identified (Russell, 1979; Galli et al., 1994).
Mutantsentirely lackingcell surfaceexpression ofc-Kit (c-KitWIW) are lethal within a
few days afterbirth(Russell, 1979). This lethality can be overcome by transplantation
of wild type hematopoietic stem cells (Mintz and Fleischman, 1979). The most
prominent pathological symptom in c-KitWIW mice is a severe macrocytic anemia
(reducedredbloodcell [RBC] numbers with increased RBC volume), and this anemia
is the putative cause ofdeath(Russell, 1979). Hence, until now, an~ses ofadult c-Kit
mutants have been limited to mild W or steel alleles. The c-Kit IW genotype was
known to be lethal in the WB mouse strain background (as well as in all other tested
backgrounds). We have identified a white, black-eyed c-KitW/W mouse, surviving to
adulthood, in out-crosses ofWB-c-KitW/+to mixed genetic backgrounds. This novel
mutant has been termed the "Vickid" mouse (Waskow et al. unpublished). The
molecular nature of the putative c-Kit suppressor mutation is unknown. Here, we
summarizeourdetailedanalysesoflymphocyte development in adult Vickid mice, and
compare these findings to the role previously recognized for c-Kit in lymphocyte
developmentduringfetal andneonatal life.
ThymocyteDevelopmentin Neonatalc-KitWIW Mice
Analysesofthymocyte development in both neonatal c-KitWIW mice, as well as
in adult wild type mice grafted with either wild type or c-Kit-ligand-deficient fetal
thymic transplants (Sl/S\) revealed that intrathymically expressed c-Kit ligand is a
major factor driving expansion ofvery immature thymocytes in vivo. Transplantation
ofSl/SI grafts was importantto separateeffectsdueto lack ofKit! at the hematopoietic
stem cell (HSC) level (as in the fetal liver of c-KitW/w mice) from intrathwmic
development (as in Sl/SI thymi grafted intowild type mice). In the neonatal c-Kit IW
thymus, and in Sl/SI thymus grafts, the size of the CD3-CD4-CD8- (triple-negative
[TN]) thymocyte compartment was reduced -40 fold and -12 fold, respectivly. This
reduction in TN cell numbers was due to diminished proliferation in the thymus as
shown by in vivo bromodeoxyuridine labeling of thymocytes in wildtype or SUSI
mutant grafts. Collectively, lack of Kit! in the thymic environment reduces the
expansion rate ofTN, but not overall thymocytes, by -50%. Apart from these clear
alterations at early stages of thymfi,Vte development, thymocyte development was
permissive in both neonatal c-KitW mice and in SI/SI thymus grafts. Thus, this
study (Rodewaldetal., 1995),togetherwith earlierinvivo work(Asamoto and Mandel,
1981), has established a role, albeit not an essential one, for c-KitiKitl interactions in
the expansionofvery earlythymic immigrants.
