Multichain Immune Recognition Receptor Signaling

From Spatiotemporal Organization to Human Disease
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Alexander Sigalov
848 g
257x170x25 mm

Immunological recognition is a central feature of the adaptive immunity of vertebrates. With the exception of agnathans, which developed an entirely distinct set of immunologically-specific molecules, all vertebrates use a recognition system based on what Achsah Keegan and I suggested in 1992 be termed multichain immune recognition receptors (MIRRs). MIRRs consist of ligand-binding molecules that are immunoglobulin supergene family members associated with signal transducers and enhancers in such a way as both insure precise ligand recognition, discrimination and ampHfication of the signal. Two of the prototypic sets of MIRRs, the T-cell and B-cell receptors, are among the most remarkable recognition molecules known. These are extraordinarily diverse molecules in which the range of ligands that can be potentially recognized prob­ ably exceeds the actual numbers of lymphocytes in the body. The discovery of the genetic basis of assembling these receptors and understanding how they bind to their cognate antigens are among the most stunning of scientific achievements. Yet these immensely specific binding chains (the heavy/light chain pair for immunoglobulin and the a/p chain pair for most T cells), when expressed as membrane molecules, have no obvious mechanism of signaling. For example, the |iH chain cytosolic do­ main consists of three amino acids (lysine-valine-lysine) and the L chain is not even embedded in the membrane. Furthermore, there is no known direct mechanism to propagate information from the binding domain of the B-cell or T-cell receptors to the membrane-proximal domains of the same chains.
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

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