How the Immune System Recognizes Self and Nonself978-4-431-73884-8/1.pdf · How the Immune System Recognizes Self and Nonself Daisuke Kitamura ... immune system might be applied to

How the Immune System Recognizes Self and Nonself

How the Immune System Recognizes Self and Nonself

Daisuke KitamuraEditor

Immunoreceptors and Their Signaling

Daisuke KitamuraProfessorDepartment of Medicinal and Life ScienceFaculty of Pharmaceutical SciencesDivision of Molecular BiologyResearch Institute for Biological SciencesTokyo University of ScienceYamazaki 2669, NodaChiba 278-0022, [email protected]

Cover design conceived by Daisuke Kitamura and executed by Chigusa Himuro

Library of Congress Control Number: 2007934529

ISBN 978-4-431-73883-1 Springer Tokyo Berlin Heidelberg New York

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in other ways, and storage in data banks.The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature.

Springer is a part of Springer Science+Business Mediaspringer.com© Springer 2008Printed in Japan

Typesetting: SNP Best-set Typesetter Ltd., Hong KongPrinting and binding: Shinano, Japan

Printed on acid-free paper

Preface

V

How do you discriminate yourself from other people? This question must sound odd to you since you easily recognize others at a glance and, without any effort, would not mistake them for yourself. However, it is not always easy for some people to discriminate themselves from others. For example, patients with schizo-phrenia often talk with “others” living inside themselves. Thus it is likely that nor-mally your brain actively recognizes and remembers the information belonging to yourself and discriminates it from the information provided by others, although you are not conscious of it. This brain function must have been particularly important for most animals to protect their lives from enemies and for species to survive through evolution. Similarly, higher organisms have also acquired their immune system through evolution that discriminates nonself pathogens and self-body to protect their lives from pathogens such as bacteria or viruses.

The brain system may distinguish integrated images of self and nonself created from many inputs, such as vision, sound, smell, and others. The immune system recognizes and distinguishes a variety of structural features of self and nonself components. The latter actually include almost everything but self: for example, bacteria, viruses, toxins, pollens, chemicals, transplanted organs, and even tumor cells derived from self-tissue. To this end the immune system recruits different kinds of immune cells, such as B and T lymphocytes, natural killer (NK) cells, dendritic cells, and macrophages. These cells have specifi c functions and are equipped with distinctive sets of receptors to recognize self and/or nonself compo-nents. B and T lymphocytes have characteristic antigen receptors whose binding specifi cities are extremely diverse among individual cells. This diversity is gener-ated through somatic rearrangement of the genes encoding the antigen receptors. The repertoires of the diverse antigen receptors cover a huge variety of self and nonself antigens, which normally results in tolerance to self antigens and the immune responses to the nonself antigens including antibody production, T-cell-mediated cytotoxicity, and infl ammation. The antigen recognition signal is critically regulated by activating or inhibitory co-receptors on the same cells. The antigens are also recognized by specifi c antibodies bound with Fc receptors on various immune cells. NK and NKT cells express collectively what are called NK receptors

composed of various pairs of receptors, one recognizing a specifi c viral or neoplas-tic antigen and the other self MHC (major histocompatibility complex) antigen on the self cells, and the pair work together to discriminate a target to kill. In addition to the NK receptors, a growing number of the paired immunoglobulin-like receptors have been identifi ed. Finally, Toll-like receptors expressed on the cells such as dendritic cells and macrophages recognize various structural patterns of pathogens to eliminate them as the fi rst defense and also to regulate the immune response by lymphocytes. Single mutations in some of these receptors or their downstream signaling molecules are known to cause autoimmune diseases in mice or humans, suggesting that functions of those immune cells expressing a different set of recep-tors are highly integrated and cooperate in an immune system to decide what is self and what is nonself.

In contrast to the extreme diversity of the receptors, the molecules involved in the signaling from such receptors is relatively limited and often is shared among different receptor systems. Therefore, the immune cells may use a common strategy for processing the signals from these receptors and for making a decision about their next action. The aim of this book is to try to clarify how the immune cells recognize through receptors a diversity of targets, being either self or nonself, how they translate this recognition into signals and transmit the signals, and how fi nally they decide to react or not to play a part in the immune response. For this purpose, an extensive and updated review on each receptor system is described in each chapter by an expert in that area. Although our knowledge is still far from complete, this challenge will give you many clues to discover the principle of the signaling machinery and to understand the complexity of cell interaction through receptor signaling in the immune system. Thus this book will help you to imagine the basic strategy of the immune system to distinguish self and nonself. I believe this chal-lenge is particularly important for basic as well as clinical immunologists who are seeking a breakthrough in the regulation of immune diseases such as autoimmunity and allergy. Also, the concept and strategy of self–nonself discrimination in the immune system might be applied to the brain system as briefl y mentioned above, or as a security system of a computer network.

I would like to thank all the authors for their invaluable contributions and their patience.

Daisuke Kitamura Noda, Japan

VI Preface

Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V

List of Authors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XI

Color Plates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XV

1 Recognition of Pathogens: Toll-Like Receptors . . . . . . . . . . . . . . . . . . 1Satoshi Uematsu and Shizuo Akira1.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2 Innate Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3 Pathogen Recognition by TLR. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51.4 Toll-Like Receptor Signaling Pathways. . . . . . . . . . . . . . . . . . . . . . 91.5 Negative Regulation of TLR Signaling . . . . . . . . . . . . . . . . . . . . . . 171.6 Conclusion and Future Prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . 22References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

2 Strategies of Natural Killer (NK) Cell Recognition and Their Roles in Tumor Immunosurveillance . . . . . . . . . . . . . . . . . . . . . 37C. Andrew Stewart and Eric Vivier2.1 Introduction: An Interesting Epistemological Case . . . . . . . . . . . . . 372.2 Natural Killer Cells in Innate Immunity . . . . . . . . . . . . . . . . . . . . . 382.3 Natural Killer Cell Recognition of “Missing-Self”: An Array of

Inhibitory Cell Surface Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . 402.4 Complexity of the “NK Cell Zipper”. . . . . . . . . . . . . . . . . . . . . . . . 442.5 Coordination of NK Cell Activating and Inhibitory Signals

in Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532.6 Programming a “Natural” Killer: Steady-State and

Situation-Specifi c Regulation of NK Effector Functions . . . . . . . . 622.7 Conclusions and Perspectives: NK Cells, “Self Versus Nonself ,”

and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

VII

3 Recent Progress on Paired Immunoglobulin-Like Receptors . . . . . . 83Hiromi Kubagawa, Ching-Cheng Chen, Ikuko Torii, Max D. Cooper, Kyoko Masuda, Yoshimoto Katsura, and Hiroshi Kawamoto3.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833.2 PIR Expression by Early Hematopoietic Cells . . . . . . . . . . . . . . . . 853.3 PIR Expression by Thymocyte Progenitors . . . . . . . . . . . . . . . . . . . 863.4 Differentiation Potential of PIR+ and PIR− Lymphoid

Progenitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 873.5 PIR Expression by Dendritic Cell Precursors . . . . . . . . . . . . . . . . . 893.6 PIR Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903.7 Paired Immunoglobulin-Like Receptor Function. . . . . . . . . . . . . . . 923.8 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

4 Self–nonself Recognition through B-Cell Antigen Receptor. . . . . . . . 99Daisuke Kitamura4.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 994.2 Signal Transduction from BCR . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1014.3 BCR Signaling Pathways for Immune Response. . . . . . . . . . . . . . . 1124.4 BCR Signaling Pathways for Self Tolerance. . . . . . . . . . . . . . . . . . 1164.5 Concluding Remarks: To Respond or Not to Respond, That is

the Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

5 How Do T Cells Discriminate Self from Nonself? . . . . . . . . . . . . . . . . 133Catherine Mazza and Bernard Malissen5.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1335.2 Structure of the TCR Complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1355.3 How Does the αβ TCR Convey Signals Across the Membrane? . . . 1405.4 TCR Assembly During Intrathymic Development . . . . . . . . . . . . . 1475.5 How TCRs Bind pMHC. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1495.6 What Causes the Restriction in Orientation Imposed on

TCR–pMHC Interactions? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1565.7 Rationalizing the Purpose of TCR αβ Positive Selection . . . . . . . . 1595.8 Recessive and Dominant Tolerance . . . . . . . . . . . . . . . . . . . . . . . . . 1615.9 Evolutionary Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

6 Fc Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173Falk Nimmerjahn and Jeffrey V. Ravetch6.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1736.2 Fc Receptors—Basic Facts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1746.3 Fc Receptor Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1786.4 Fc Receptor Biology In Vivo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

VIII Contents

6.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192

7 Self and Nonself Recognition by Coreceptors on B Lymphocytes: Regulation of B lymphocytes by CD19, CD21, CD22, and CD72 . . . 199Kozo Watanabe and Takeshi Tsubata7.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1997.2 Regulation of B Cells by CD19/CD21 Complex. . . . . . . . . . . . . . . 2007.3 Regulation of B Cells by CD22 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2067.4 Regulation of B Cells by CD72 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2107.5 Self and Nonself Recognition by Coreceptors on B cells . . . . . . . . 212References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

8 Co-Receptors in the Positive and Negative Regulation of T-Cell Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221Helga Schneider and Christopher E. Rudd8.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2218.2 Positive Co-stimulatory Molecules . . . . . . . . . . . . . . . . . . . . . . . . . 2248.3 Negative Co-stimulatory Molecules. . . . . . . . . . . . . . . . . . . . . . . . . 2298.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

Contents IX

List of Authors

XI

Shizuo AkiraDepartment of Host Defense, Research Institute for Microbial Diseases, Osaka

University, Osaka 565-0851, Japan; ERATO, Japan Science and Technology Corporation, Suita, Osaka 565-0871, Japan

Ching-Cheng ChenDivision of Developmental and Clinical Immunology, University of Alabama at

Birmingham, Birmingham, AL 35294-3300, USA

Max D. CooperHoward Hughes Medical Institute, Birmingham, AL, USA

Yoshimoto KatsuraDivision of Cell Regeneration and Transplantation, Advanced Medical Research

Center, Nihon University School of Medicine, Tokyo 173-8610, Japan

Hiroshi KawamotoLaboratory for Lymphocyte Development, RIKEN Research Center for Allergy

and Immunology, Yokohama, Kanagawa 230-0045, Japan

Daisuke KitamuraDepartment of Medicinal and Life Science, Faculty of Pharmaceutical Sciences,

Division of Molecular Biology, Research Institute for Biological Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan

Hiromi KubagawaDivision of Developmental and Clinical Immunology, University of Alabama at

Birmingham, Birmingham, AL 35294-3300, USA

Bernard MalissenCentre d’Immunologie de Marseille-Luminy, INSERM, U631. CNRS, UMR6102,

Université de la Méditerrannée, 13288 Marseille Cedex 9, France

Kyoko MasudaLaboratory for Lymphocyte Development, RIKEN Research Center for Allergy and

Immunology, Yokohama, Kanagawa 230-0045, Japan

Catherine MazzaCentre d’Immunologie de Marseille-Luminy, INSERM, U631. CNRS, UMR6102,

Université de la Méditerrannée, 13288 Marseille Cedex 9, France

Falk NimmerjahnLaboratory of Molecular Genetics and Immunology, Rockefeller University, New

York, NY 10021, USA; Laboratory of Experimental Immunology and Immunotherapy, University of Erlangen-Nuernberg, Nikolaus-Fiebiger-Center for Molecular Medicine, 91054 Erlangen, Germany

Jeffrey V. RavetchLaboratory of Molecular Genetics and Immunology, Rockefeller University,

New York, NY 10021, USA

Christopher E. RuddCell Signalling Section, Division of Immunology, Department of Pathology,

University of Cambridge, Cambridge, CB2 1QP, UK

Helga SchneiderCell Signalling Section, Division of Immunology, Department of Pathology,

University of Cambridge, Cambridge, CB2 1QP, UK

C. Andrew StewartLaboratory of NK cells and Innate Immunity, Centre d’Immunologie de Marseille-

Luminy, INSERM, U631. CNRS, UMR6102, Université de la Méditerranée, 13288 Marseille Cedex 9, France

Ikuko ToriiDivision of Developmental and Clinical Immunology, University of Alabama at

Birmingham, Birmingham, AL 35294-3300, USA

Takeshi TsubataLaboratory of Immunology, School of Biomedical Science and Department of

Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan

Satoshi UematsuDepartment of Host Defense, Research Institute for Microbial Diseases, Osaka

University, Suita, Osaka 565-0851, Japan

Eric VivierLaboratory of NK Cells and Innate Immunity, Centre d’Immunologie de Marseille-

Luminy, INSERM, U631. CNRS, UMR6102, Université de la Méditerranée, 13288 Marseille Cedex 9, France; Hôpital de la Conception, Assistance Publi-que-Hôpitaux de Marseille, 13005 Marseille, France

XII List of Authors

Kozo WatanabeLaboratory of Immunology, School of Biomedical Science and Department of

Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan

List of Authors XIII

MyD88-dependentpathway

MyD88-independentpathway

Endosome

TIRAP/Mal TRAM

MyD88 TRIF

IKKi

MD2TLR4

IRAK-4IRAK-1

TRAF6

IκBNF-κB

TBK1

IRF3

TLR3TLR7TLR8TLR9

TRIF

MyD88

IRAK-1

TRAF6

IRAK-4

membrane

nucleus

IRF7

Inflammatorycytokines

IFN-βIFN-inducible genes

IFN-αs & IFN-βIFN-inducible genes

IκBNF-κB

Inflammatorycytokines

Specific pathway in plasmacytoid DCs

(Fig. 1.2, p. 10)

Color Plates

JNK

ERK

PKCββ

p38IKKα

NF-κBNFATJun

PI(4,5)P2

Vav

SykLyn

Grb

2

BtkRas

Rac

IP3 DAGBL

NK

MEK

Raf

β α

Ca2+

PLCγ2

calcineurin

PI3KBCAP

PI(3,4,5)P3

CD

19

CARMA1

Bcl10

MALT1

IKKβ

IKKγ -Ub

Iκ B

p50

c-Rel

-Ub-Ub-Ub

IκB

NFAT

Akt

RasGRP

NF-κB

Elk1ATF2

CD

22

CD

72

SHP-1YY

YY

?

TAK1

HPK1

B cell receptor

(Fig. 4.3, p. 104)

XV

Human

NK cellsTarget

CD16 Fcγ

Viral hemagglutinins, ?NKp46, NKp44

NKG2D ULBP/RAET,MICA, MICB

HLA-C, ?KIR-S

CD94/NKG2C HLA-E

HLA-ECD94/NKG2E

CRACC

CD244 (2B4)

CD2

NTBA

CD48

CD48, CD58

NTBA

?

CS1 CS1

α4β1 integrin VCAM-1 (CD106)

βββ1 integrins

ICAM1 (CD54)ICAM2 (CD102)

ββ2 integrins

Receptors or putative receptors for HLAclass I or relatedmolecules

CD160 (BY55) HLA-C

Fibronectin

Fibronectin

Fibrinogen

Laminin

CD2 family

CD59

NKp80

C8,C9

AICL

CD155 (Ncl5)CD96 (Tactile)

CD226 (DNAM-1) CD112 (Nectin-2), CD155 (Ncl5)Receptors fornectins ornectin-likemolecules

Natural CytotoxicityReceptors (NCR)

ADCC Receptor

ICAM1 (CD54)

Fibrinogen

iC3bICAM1 (CD54), CD23

iC3b, β-Glucan

NKp30

CRTAM Ncl2

pp65, ?

CD70CD27

LFA-1 (CD11a/CD18)

CR3 (CD11b/CD18)

α5β1 integrin

CR4 (CD11c/CD18)

α6β1 integrin

Mouse

NK cellsTarget

Viral hemagglutinins, ?

LFA-1 (CD11a/CD18)ICAM1 (CD54)

ICAM2 (CD102)

CR3 (CD11b/CD18)Fibrinogen

ICAM1 (CD54)

CR4 (CD11c/CD18)

Fibrinogen

iC3bICAM1 (CD54), CD23

iC3b, β-Glucan

Act KLRA (Act Ly49)

KLRK1 (NKG2D)

KLRD1/KLRC2(CD94/NKG2C)

Qa-1?

Qa-1?KLRD1/KLRC3(CD94/NKG2E)

CD16 Fcγ

?

MCMV m157 (Ly49H),H2-Dd (Ly49D)

extracellular matrixproteins

β-1 integrins

CD99-like moleculePILRα

MHC class II moleculesLAG-3

Clr-g

?

H60, Rae1, MULT-1

MAR1 (NCR1/mNKp46)

DNAM-1 (CD226)

CD70CD27

CD112 (Nectin-2), CD155 (Ncl5)

NKRP-1F

NKRP-1C

NKRP1-A

(Fig. 2.4, p. 50)

Color Plates XVII

(Fig. 4.4, p. 113)

Primary foci

MemoryB cells

PALS (T-cell zone)

B cell follicle Marginalzone

Dark zone

Light zone

Clonalexpansion

Somatichypermutation

Clonal expansionClass switching

Germinalcenter

Long-livedplasma cells

Short-livedplasma cells

Plasma-blasts

Centroblasts

Centrocytes

TH

P

P

Activation

P

TI-II antigen

IgM

IgG

IgG

B

DC

TH

THBm

B

TH

Bm

Recallresponse

Affinityselection

FDC

Antigenpresentation

TD antigen

BB

BTH

IgG

IgM

Affinity selection

Pb

PbHigh

XVIII Color Plates

(Fig. 8.1, p. 222)

(Fig. 5.1, p. 136)