This book intends to assemble reviews on the progress in defining and controlling the spatiotemporal organization of key events in immune cell activation. Improved understanding of MIRR-mediated signaling has a number of potential practical applications, from the rational design of drugs and vaccines to the engineering of cells for biotechnological purposes. In Section 1, spatial organization and physiological function of the MIRR family members such as T cell receptor (TCR), B cell receptor (BCR), Fc receptors, natural killer (NK) cell receptors, and platelet glycoprotein VI (GPVI) will be reviewed. Section 2 will focus on current models of MIRR-triggering and highlight modern technologies to visualize cell-cell interaction contacts such as immunological synapse and to measure protein-protein interactions in space in real time. Potential therapeutic strategies targeting the MIRR-mediated transmembrane signal transduction will be shortly reviewed in Section 3. This book will summarize our current knowledge in this field and illustrate how control of the MIRR-triggered signaling could become a potential target of medical intervention, thus bridging basic and clinical immunology.

"This book intends to assemble reviews on the progress in defining and controlling the spatiotemporal organization of key events in immune cell activation. Improved understanding of MIRR-mediated signaling has a number of potential practical applications, from the rational design of drugs and vaccines to the engineering of cells for biotechnological purposes. In Section 1, spatial organization and physiological function of the MIRR family members such as T cell receptor (TCR), B cell receptor (BCR), Fc receptors, natural killer (NK) cell receptors, and platelet glycoprotein VI (GPVI) will be reviewed. Section 2 will focus on current models of MIRR-triggering and highlight modern technologies to visualize cell-cell interaction contacts such as immunological synapse and to measure protein-protein interactions in space in real time. Potential therapeutic strategies targeting the MIRR-mediated transmembrane signal transduction will be shortly reviewed in Section 3. This book will summarize our current knowledge in this field and illustrate how control of the MIRR-triggered signaling could become a potential target of medical intervention, thus bridging basic and clinical immunology."

Foreword; William Paul
Preface; Alexander B. Sigalov

Section I. MIRRs: Structure and Physiological Function

1. T-Cell Receptor; Jose M. Rojo, Raquel Bello and Pilar Portolés

Abstract

Introduction

Minimal Components and Stoichiometry of the TCR/CD3 Complex

TCR Clusters on the Cell Surface

Topology of Chain Interactions within TCR/CD3 Complexes

Interactions between the TCR and Antigen-Role of CD4 and CD8 Coreceptors

Other TCRs

Are All TCRs Equal, or Are Some TCRs More Equal Than Others?

Future Directions

2. B-Cell Receptor; Randall J. Brezski and John G. Monroe

Abstract

Introduction

Structure of the BCR

B-Cell Development

Molecular Aspects of Ligand-Induced BCR Signal Transduction

Membrane Compartmentalization of the BCR

Balance between Positive and Negative Regulators of BCR Signaling

Ligand-Independent BCR-Induced Tonic Signaling

Conclusion

3. Fc Receptors; Maree S. Powell and P. Mark Hogarth

Abstract

Introduction

Human receptors for immunoglobulin

Interaction between Fc receptor and immunoglobulin

Spatial organization of FcRs

Physiological function of Fc receptors

Concluding comments

4. Natural Killer Cell Receptors; Roberto Biassoni

Abstract

Introduction

Inhibitory Receptors

Activating Receptors

Conclusions

5. Platelet Glycoprotein VI; Stephanie M. Jung and Masaaki Moroi

Abstract

Introduction

Structure of GPVI

Interaction of GPVI with collagen

GPVI-mediated signal transduction

Physiological Function of GPVI

Summary and perspectives

Section II. MIRR Signaling: Possible Mechanisms and the Techniques to Study and Visualize

6. Clustering Models; Wolfgang W.A. Schamel and Michael Reth

Abstract

Introduction

Homoclustering

Heteroclustering

Pseudodimer Model

Homo- and Heteroclustering and Lipid Rafts

The PreTCR and PreBCR

7. Segregation Models; Elaine P. Dopfer, Mahima Swamy, Gabrielle M. Siegers, Eszter Molnar, Jianying Yang and Wolfgang W.A. Schamel

Abstract

Introduction

Lipid Rafts

Segregation by Raft Clustering

Kinetic-Segregation Model

Immune Synapse and Microclusters

8. Kinetic Proofreading Model; Byron Goldstein, Daniel Coombs, James R. Faeder and William S. Hlavacek

Abstract

Introduction

Kinetic proofreading illustrated through FceRI signaling

The extent of kinetic proofreading in FceRI signaling

Some responses may escape kinetic proofreading

McKeithan's mathematical formulation

T-Cell activation and the competition between kinetic proofreading and serial engagement

Concluding remarks

9. Serial Triggering Model; Jacob Rachmilewitz

Abstract

T-Cell Receptor Signaling Cascade

Serial Triggering Model

Flexible and hierarchical T-Cell Activation Thresholds

Temporal Summation as a mechanism for Signal Integration

Summary

10. Conformational Model; Ruth M. Risueño, Angel R. Ortiz and Balbino Alarcón

Abstract

Introduction

Evidence in Favour of Conformational Changes in MIRRs

Consequences for Ligand Recognition

Model for Transmission of Conformational Changes

Conclusions

11. Permissive Geometry Model; Susana Minguet and Wolfgang W.A. Schamel

Abstract

Introduction

The clustering model of TCR triggering

Oligomeric MIRRs

Conformational changes within the MIRRs

Permissive geometry model

Agonist/self-peptide-MHC heterodimers

12. Signaling Chain Homoligomerization (Schol) Model; Alexander B. Sigalov

Abstract

Introduction

Central Hypothesis

Schol Model of MIRR Signaling

Conclusions

13. Visualization of Cell-Cell Interaction: Contacts-Synapses and Kinapses; Michael L. Dustin

Abstract

Introduction

New model for sustained signaling through the synapse

In vivo functions of synapse and kinapse

In vivo Analysis of CD4+ T-Cell Priming and Tolerance Induction

In vivo analysis of CD8+ T-Cell priming and tolerance induction

Priming vs. tolerance

Dynamics of CD4+ T-Cell Help for CD8+ T-Cell responses

Effector sites

Summary

14. Visualization of Protein Interactions in Living Cells; Tomasz Zal

Abstract

Introduction

FRET

Bimolecular Fluorescence complementation

Fluorescence correlation techniques

Fluorescent labeling of proteins in living cells

Quantitative FRET imaging

Using FRET to analyze receptor (re)arrangements

Imaging TCR-coreceptor interactions in the immunological synapse

Affinity versus random collisions: acceptor titration FRET

Mathematical model of FRET for simultaneous complex formation and random collisions

Conclusion

Section III. MIRR Signaling and Therapy of Immune Disorders

15. Immunogenicity in Peptide-Immunotherapy: From Self/Nonself to Similar/Dissimilar Sequences; Darja Kanduc

Abstract

Introduction

The Question: What Renders a peptide immunogenic?

From a Historical Point of View-The Immune Response and Self/Nonself Sequences

From a Logical Point of View-The Immune Response and Similar/Dissimilar Sequences

Browsing through Literature: Similarity Level of Identified Epitopes

Concluding Remarks

16. Therapeutic Aplication of Transmembrane T and Natural Killer Cell Receptor Peptides; Nicholas Manolios, Marina Ali, Michael Amon and Veronika Bender

Abstract

Introduction

Therapeutic Application

Biophysical Attributes of CP

Biological Features of CP

Peptide Bioavailability

Effects of CP Conjugation

Conclusion

17. Fc Receptor Targeting in the Treatment of Allergy, Autoimmune Diseases and Cancer; Akira Nakamura, Tomohiro Kubo and Toshiyuki Takai

Abstract

Introduction

FcR function

FcR-targeting therapy

Conclusion

18. Therapeutic Blockade of T-Cell Antigen Receptor Signal Transduction and Co-stimulation in Autoimmune Disease; Joseph R. Podojil, Danielle M. Turley and Stephen D. Miller

Abstract

Introduction

T-Cell activation: target for treatment of disease

Coupled-cell tolerance: antigen-specific induction of tolerance to a self-antigen

Immune synapse: activation of the TCR in lipid rafts

NFAT: Regulation of T-Cell activation and anergy

NFAT inhibitors: putative therapeutics

LAT: an Alternative component of TCR signaling

Conclusions

19. MHC and MHC-Like Molecules: Structural Perspectives on the Design of Molecular Vaccines; Vasso Apostolopoulos, Eliada Lazoura and Minmin Yu

Abstract

Introduction

Stimulation of CD8 T Cells

MHC class I molecules

Noncanonical features of peptide-binding to MHC class I molecules

Stimulation of CD4 T Cells

MHC Class II Molecules

MHC class III molecules

MHC gene mutations

Nonclassical MHC Class I Molecules

Nonclassical MHC Class II Molecules

MHC-Peptide Interaction with the TCR

MHC Class I-like Molecules

Future Prospects

20. SCHOOL Model and New Targeting Strategies; Alexander B. Sigalov

Abstract

Introduction

Long-Standing Mystery of MIRR Triggering and Transmembrane Signaling

SCHOOL Model of MIRR Triggering and Signaling: Basic Concept, Major Driving Forces, Restraints and Advantages

SCHOOL Model: New Intervention Points for MIRR-Mediated Immune Disorders

Conclusions

21. Immune Receptor Signaling, Aging and Autoimmunity; Anis Larbi, Tamas Fülöp and Graham Pawelec

Abstract

Introduction

Immunosenescence

Receptor Signaling in Immunosenescence

The Role of Membrane Rafts in TCR Signaling: The Aging Rafts

Heterogeneity in Membrane Rafts and T-cell Subsets

MIRR Signaling and Autoimmunity

Therapeutic Strategies Targeting the MIRR Signaling

Conclusion

22. Viral Pathogenesis, Modulation of Immune Receptor Signaling and Treatment; Walter M. Kim and Alexander B. Sigalov

Abstract

Introduction

Viruses: Classification and Pathogenesis

Viral Entry and Membrane Targeting

Viral Replication

Translation of Redundant Viral Strategies into Disease Care

Conclusions and Perspectives