Antigen Presenting Cells Edited by Harald Kropshofer and Anne B. Vogt Related Titles R. A. Meyers (Ed.) Encyclopedia of Molecular Cell Biology and Molecular Medicine, 2nd Edition 2005 ISBN 3-527-30542-4 M. Lutz, N. Romani, A. Steinkasserer Handbook of Dendritic Cells – Biology, Diseases, and Therapy 2006 ISBN 3-527-31109-2 J. R. Kalden, M. Herrmann Apoptosis and Autoimmunity – From Mechanisms to Treatments 2003 ISBN 3-527-30442-8 S. H. E. Kaufmann Novel Vaccination Strategies 2004 ISBN 3-527-30523-8 A. Hamann, B. Engelhardt Leukocyte Trafficking – Mechanisms, Therapeutic Targets, and Methods 2005 ISBN 3-527-31228-5 Antigen Presenting Cells From Mechanisms to Drug Development Edited by Harald Kropshofer and Anne B. Vogt Editors PD Dr. Harald Kropshofer Roche Centre for Medical Genomics Building 86/805 F. Hoffmann-La Roche AG Grenzacherstr. 124 4070 Basel Switzerland Dr. Anne B. Vogt Roche Centre for Medical Genomics Building 86/804 F. Hoffmann-La Roche AG Grenzacherstr. 124 4070 Basel Switzerland & All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Library of Congress Card No.: applied for British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. Bibliographic information published by Die Deutsche Bibliothek Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data is available in the Internet at <http://dnb.ddb.de>. � 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – nor transmitted or translated into machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Printed in the Federal Republic of Germany. Printed on acid-free paper. Typesetting K�hn & Weyh, Satz und Medien, Freiburg Printing betz-druck GmbH, Darmstadt Bookbinding J. Sch�ffer GmbH, Gr�nstadt ISBN-13: 978-3-527-31108-8 ISBN-10: 3-527-31108-4 V Preface XV List of Contributors XIX List of Abbreviations XXIII Color Plates XXVII Part I Antigen Presentation in the Immune System 1 1 Some Old and Some New Findings on Antigen Processing and Presentation 3 Emil R. Unanue 1.1 Introduction 3 1.2 HEL Processing 4 1.3 Selection of Peptide Segments of HEL 9 1.4 HEL: Conformational Isomers 11 1.4.1 Biology of Type B T Cells 15 1.5 Negative Selection and Peripheral Activation to HEL Peptides 16 1.6 Response to HEL Immunization in the Draining Lymph Node 17 Part II Molecular Mechanisms of Antigen Processing 25 2 Antigen Entry Routes – Where Foreign Invaders Meet Antigen Presenting Cells 27 Percy A. Knolle 2.1 Introduction 27 2.2 Antigen Entry via the Gastrointestinal Tract 28 2.2.1 Peyer’s Patches 29 2.2.2 Mesenteric Lymph Node 30 2.2.3 Dendritic Cells of the Lamina Propria 31 2.2.4 Pathogens Target Intestinal Antigen Presenting Cells 33 Contents VI 2.3 Antigen Entry via the Skin 35 2.4 Systemic Dissemination of Antigens/Infectious Microorganisms 38 2.5 Antigen Presenting Cells in the Liver 39 2.5.1 Dendritic Cells 39 2.5.2 Kupffer Cells 41 2.5.3 Liver Sinusoidal Endothelial Cells 42 2.6 Conclusion 44 3 Antigen Processing in the Context of MHC Class I Molecules 51 Frank Momburg 51 3.1 Tracing the Needle in the Haystack: The Efficiency of Antigen Processing and Presentation by MHC Class I Molecules 51 3.2 The “Classical” Route: Loading of MHC Class I Molecules With Peptides Generated in the Cytoplasm 53 3.2.1 Cytosolic Peptide Processing by Proteasomes and other Proteases 53 3.2.1.1 Structure and Function of the Proteasomal Core and Interferon- induced Subunits 56 3.2.1.2 Targeting Proteins for ATP-dependent Degradation by 26S Proteasomes 56 3.2.1.3 Cleavage Properties of (Immuno)Proteasomes 57 3.2.1.4 Peptide Processing by Nonproteasomal Cytosolic Peptidases 59 3.3 Crossing the Border – Peptide Translocation into the ER by TAP 60 3.3.1 Structure and Function of TAP 60 3.3.2 Substrate Specificity of TAP 62 3.3.3 TAP-independent Peptide Entry into the ER 63 3.4 Fitting in the Best: TAP-associated Peptide Loading Complex Optimizes MHC-I Peptide Binding 63 3.4.1 Structure of MHC-I Molecules 64 3.4.2 Early Steps in the Maturation of MHC-I Molecules 64 3.4.3 Structure and Molecular Interactions of Tapasin 66 3.4.4 Optimization of Peptide Loading in the TAP-associated Loading Complex 67 3.5 On the Way Out: MHC-I Antigen Processing along the Secretory Route 70 3.6 Closing the Circle – Cross-presentation of Endocytosed Antigens by MHC-I Molecules 73 3.6.1 Phagosome-to-cytosol Pathway of MHC-I Peptide Loading 73 3.6.2 Endolysosomal Pathway of MHC-I Peptide Loading 76 4 Antigen Processing for MHC Class II 89 Anne B. Vogt, Corinne Ploix and Harald Kropshofer 4.1 Introduction 89 4.2 Types of Antigen Presenting Cells 90 Contents VII 4.2.1 Macrophages, B Lymphocytes and DCs 90 4.2.2 Tissue-resident APCs 91 4.2.3 Maturation State of APCs 92 4.2.3.1 Immature APCs 92 4.2.3.2 Mature APCs 92 4.3 Antigen Uptake by APCs 93 4.3.1 Macropinocytosis 93 4.3.2 Phagocytosis 94 4.3.3 Receptors for Endocytosis 95 4.4 Generation of Antigenic Peptides 97 4.4.1 Reduction of Disulfide Bonds: GILT 97 4.4.2 Regulation of the Proteolytic Milieu 98 4.4.3 Protease/MHC Interplay in Antigen Processing 99 4.5 Assembly of MHC II Molecules 102 4.5.1 Structural Requirements of MHC II 102 4.5.2 Biosynthesis of MHC II 103 4.5.3 Chaperones for Peptide Loading 104 4.5.3.1 HLA-DM/H2-DM 104 4.5.3.2 HLA-DO/H2-DO 107 4.6 Export of MHC II and Organization on the Cell Surface 109 4.6.1 Membrane Microdomains 109 4.6.2 Tubular Transport 112 4.7 Viral and Bacterial Interference 114 4.8 Concluding Remarks 116 5 Antigen Processing and Presentation by CD1 Family Proteins 129 Steven A. Porcelli and D. Branch Moody 5.1 Introduction 129 5.2 CD1 Genes and Classification of CD1 Proteins 129 5.3 Structure and Biosynthesis of CD1 Proteins 130 5.3.1 Three-dimensional (3D) Structures of CD1 Proteins 132 5.3.2 Molecular Features of CD1–Lipid Complexes 133 5.3.3 CD1 Pockets and Portals 135 5.4 Foreign Lipid Antigens Presented by Group 1 CD1 136 5.5 Self Lipid Antigens Presented by CD1 137 5.6 Group 2 CD1-restricted T Cells 138 5.6.1 Antigens Recognized by Group 2 CD1-restricted T Cells 139 5.7 Tissue Distribution of CD1 Proteins 140 5.8 Subcellular Distribution and Intracellular Trafficking of CD1 140 5.8.1 Trafficking and Localization of CD1a 141 5.8.2 Trafficking and Localization of CD1b 141 5.8.3 Trafficking and Localization of CD1c 143 5.8.4 Trafficking and Localization of CD1d 144 5.8.5 Trafficking and Localization of CD1e 145 Contents 5.9 Antigen Uptake, Processing and Loading in the CD1 Pathway 146 5.9.1 Cellular Uptake of CD1-presented Antigens 146 5.9.2 Endosomal Processing of CD1-presented Antigens 147 5.9.3 Accessory Molecules for Endosomal Lipid Loading of CD1 148 5.9.4 Non-endosomal Loading of Lipids onto CD1 Molecules 149 5.10 Conclusions 150 Part III Antigen Presenting Cells’ Ligands Recognized by T- and Toll-like Receptors 157 6 Naturally Processed Self-peptides of MHC Molecules 159 Harald Kropshofer and Sebastian Spindeldreher 6.1 Introduction 159 6.2 Milestone Events 160 6.2.1 Nomenclature 160 6.2.1.1 Autologous Peptides 160 6.2.1.2 Endogenous Peptides 161 6.2.1.3 Natural Peptides Ex Vivo and In Vitro 161 6.2.2 Extra Electron Density Associated to MHC Molecules 162 6.2.3 Acidic Peptide Elution Approach 163 6.2.4 First Natural Foreign Peptides on MHC Class II 165 6.2.5 First Natural Viral Epitopes on MHC Class I 165 6.2.6 Self-peptide Sequencing on MHC Class I: the First Anchor Motifs 166 6.2.7 First Murine MHC Class II-associated Self-peptides: Nested Sets 167 6.2.8 First Human MHC Class II-bound Self-peptides: Hydrophobic Motifs 169 6.3 Progress in Sequence Analysis of Natural Peptides 172 6.3.1 Edman Microsequencing 172 6.3.2 Electrospray Ionization Tandem Mass Spectrometry 173 6.3.3 Automated Tandem Mass Spectrometry 175 6.3.4 MAPPs: MHC-associated Peptide Proteomics 176 6.4 Natural Class II MHC-associated Peptides from Different Tissues and Cell-types 177 6.4.1 Peripheral Blood Mononuclear Cells 177 6.4.2 Myeloid Dendritic Cells 178 6.4.3 Medullary Thymic Epithelial Cells 179 6.4.4 Splenic APCs 181 6.4.5 Tumor Cells 181 6.4.6 Autoimmunity-related Epithelial Cells 182 6.5 The CLIP Story 183 6.5.1 CLIP in APCs Lacking HLA-DM 184 6.5.2 Flanking Residues and Self-release of CLIP 184 6.5.3 CLIP in Tetraspan Microdomains 185 Contents VIII 6.5.4 CLIP as an Antagonist of TH1 Cells 188 6.6 Outlook: Natural Peptides as Diagnostic or Therapeutic Tools 189 7 Target Cell Contributions to Cytotoxic T Cell Sensitivity 199 Tatiana Lebdeva, Michael L. Dustin and Yuri Sykulev 199 7.1 Introduction 199 7.2 Intercellular Adhesion Molecule 1 (ICAM-1) 200 7.2.1 Adhesion Molecules on the Surface of APC and Target Cells 200 7.2.2 ICAM-1 Structure and Topology on the Cell Surface 200 7.2.3 ICAM-1 as Co-stimulatory Ligand and Receptor 201 7.2.4 ICAM-1-mediated Signaling 203 7.2.5 Role of ICAM-1 in Endothelial Response to Leukocytes 206 7.2.6 ICAM-1 Association with Lipid Rafts 206 7.3 Major Histocompatability Complex (MHC) 208 7.3.1 MHC Molecules 208 7.3.2 Molecular Associations of MHC-I Molecules 208 7.3.3 Association of MHC-I and ICAM-1 211 7.3.4 Could APC and Target Cells Play an Active Role in Ag Presentation? 212 7.3.5 Identical pMHCs are Clustered in the Same Microdomain 212 7.3.6 Identical pMHC can be Recruited to the Same Microdomain During Target Cell–T Cell Interaction 213 7.3.7 Co-clustering of MHC and Accessory Molecules 213 7.3.8 Role of Cytoskeleton 214 7.4 Conclusion 215 8 Stimulation of Antigen Presenting Cells: from Classical Adjuvants to Toll-like Receptor (TLR) Ligands 221 Martin F. Bachmann and Annette Oxenius 8.1 Synopsis 221 8.2 Pathogen-associated Features that Drive Efficient Immune Responses 221 8.3 Composition and Function of Adjuvants 222 8.4 TLR Protein Family in Mammals 224 8.4.1 TLR4 226 8.4.2 TLR2 227 8.4.3 TLR5 227 8.4.4 TLR11 228 8.4.5 TLR12 and TLR13 228 8.4.6 Nucleic Acids as PAMPs 228 8.4.6.1 TLR3 228 8.4.6.2 TLR7 and TLR8 229 8.4.6.3 TLR9 229 Contents IX