Mechanistic insight into lymphocyte activation through quantitative imaging and theoretical modelling.

Increasingly, it is apparent that in order to understand the complexity of immunosurveillance at the cell-cell junction, quantitative analysis at the single cell level is necessary. The visualisation of the large-scale rearrangement of proteins characterising what is known as the immunological synapse (IS) was an important discovery shaping our understanding of the events occurring during immune recognition. The use of supported planar bilayers and geometrically designed substrates combined with advanced imaging techniques such as total internal reflection fluorescence (TIRF) and Förster resonance energy transfer (FRET) has provided insight into the spatio-temporal dynamics of receptor signalling and the role of receptor trafficking in regulating cell signalling. Theoretical modelling will play a key role in the integration of such quantitative data providing mechanistic insight into lymphocyte activation.

[1]  M. Schindler,et al.  Lateral diffusion of lectin receptors in fibroblast membranes as a function of cell shape. , 1989, Experimental cell research.

[2]  Junsang Doh,et al.  Immunological synapse arrays: patterned protein surfaces that modulate immunological synapse structure formation in T cells. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Rajat Varma,et al.  Actin and agonist MHC–peptide complex–dependent T cell receptor microclusters as scaffolds for signaling , 2005, The Journal of experimental medicine.

[4]  Michael Loran Dustin,et al.  Immature CD4(+)CD8(+) thymocytes form a multifocal immunological synapse with sustained tyrosine phosphorylation. , 2002, Immunity.

[5]  Y. Louzoun,et al.  Cell surface dynamics: the balance between diffusion, aggregation and endocytosis. , 2006, Systems biology.

[6]  Borivoj Vojnovic,et al.  Imaging protein-protein interactions by multiphoton FLIM , 2003, European Conference on Biomedical Optics.

[7]  M. Neil,et al.  Microclusters of inhibitory killer immunoglobulin–like receptor signaling at natural killer cell immunological synapses , 2006, The Journal of cell biology.

[8]  M. Sheetz,et al.  Truncation mutants define and locate cytoplasmic barriers to lateral mobility of membrane glycoproteins. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Z. Lou,et al.  A Balance between Positive and Negative Signals in Cytotoxic Lymphocytes Regulates the Polarization of Lipid Rafts during the Development of Cell-Mediated Killing , 2000, The Journal of experimental medicine.

[10]  S. Bromley,et al.  The immunological synapse: a molecular machine controlling T cell activation. , 1999, Science.

[11]  M. Neuberger,et al.  B cells acquire antigen from target cells after synapse formation , 2001, Nature.

[12]  Nigel J Burroughs,et al.  Ligand detection and discrimination by spatial relocalization: A kinase-phosphatase segregation model of TCR activation. , 2006, Biophysical journal.

[13]  Arup K Chakraborty,et al.  The Immunological Synapse Balances T Cell Receptor Signaling and Degradation , 2003, Science.

[14]  Michael Meyer-Hermann,et al.  Geometrically Repatterned Immunological Synapses Uncover Formation Mechanisms , 2006, PLoS Comput. Biol..

[15]  Bridget S Wilson,et al.  Markers for detergent-resistant lipid rafts occupy distinct and dynamic domains in native membranes. , 2004, Molecular biology of the cell.

[16]  Jay T. Groves,et al.  Synaptic pattern formation during cellular recognition , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Bridget S. Wilson,et al.  Plasma membrane-associated proteins are clustered into islands attached to the cytoskeleton , 2006, Proceedings of the National Academy of Sciences.

[18]  S. Singer,et al.  The Fluid Mosaic Model of the Structure of Cell Membranes , 1972, Science.

[19]  Ronald D. Vale,et al.  Single-Molecule Microscopy Reveals Plasma Membrane Microdomains Created by Protein-Protein Networks that Exclude or Trap Signaling Molecules in T Cells , 2005, Cell.

[20]  N. Burroughs,et al.  Differential segregation in a cell-cell contact interface: the dynamics of the immunological synapse. , 2002, Biophysical journal.

[21]  E. Ikonen,et al.  Functional rafts in cell membranes , 1997, Nature.

[22]  A. Chakraborty,et al.  Low T cell receptor expression and thermal fluctuations contribute to formation of dynamic multifocal synapses in thymocytes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[23]  B. Vilen,et al.  Independent Trafficking of Ig-α/Ig-β and μ-Heavy Chain Is Facilitated by Dissociation of the B Cell Antigen Receptor Complex 1 , 2005, The Journal of Immunology.

[24]  Mark M. Davis,et al.  Imaging synapse formation during thymocyte selection: inability of CD3zeta to form a stable central accumulation during negative selection. , 2002, Immunity.

[25]  A. Dinner,et al.  B Cell Antigen Receptor Signaling and Internalization Are Mutually Exclusive Events , 2006, PLoS biology.

[26]  V. Barr,et al.  Persistence of Cooperatively Stabilized Signaling Clusters Drives T-Cell Activation , 2006, Molecular and Cellular Biology.

[27]  Tetsuo Yamazaki,et al.  T cell receptor ligation induces the formation of dynamically regulated signaling assemblies , 2002, The Journal of cell biology.

[28]  Michael Loran Dustin,et al.  CD80 Cytoplasmic Domain Controls Localization of CD28, CTLA-4, and Protein Kinase Cθ in the Immunological Synapse1 , 2005, The Journal of Immunology.

[29]  Rajat Varma,et al.  T cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. , 2006, Immunity.

[30]  Takashi Saito,et al.  Newly generated T cell receptor microclusters initiate and sustain T cell activation by recruitment of Zap70 and SLP-76 , 2005, Nature Immunology.

[31]  S. Pierce.  Lipid rafts and B-cell activation , 2002, Nature Reviews Immunology.

[32]  D. Marguet,et al.  Lipid rafts and the initiation of T cell receptor signaling. , 2005, Seminars in immunology.

[33]  M. Davis,et al.  Differential clustering of CD4 and CD3zeta during T cell recognition. , 2000, Science.

[34]  T. Zal,et al.  Altered peptide ligands induce delayed CD8-T cell receptor interaction--a role for CD8 in distinguishing antigen quality. , 2006, Immunity.

[35]  F. Batista,et al.  B‐cell activation by membrane‐bound antigens is facilitated by the interaction of VLA‐4 with VCAM‐1 , 2006, The EMBO journal.

[36]  J. Goldman,et al.  B Cell Ligand Discrimination Through a Spreading and Contraction Response , 2006, Science.

[37]  B. Nichols,et al.  Lipid raft proteins have a random distribution during localized activation of the T-cell receptor , 2004, Nature Cell Biology.

[38]  A. Kusumi,et al.  Confined lateral diffusion of membrane receptors as studied by single particle tracking (nanovid microscopy). Effects of calcium-induced differentiation in cultured epithelial cells. , 1993, Biophysical journal.

[39]  Philippos K. Tsourkas,et al.  Mechanisms of B-cell synapse formation predicted by Monte Carlo simulation. , 2006, Biophysical journal.

[40]  Mark M Davis,et al.  Dynamics of p56lck translocation to the T cell immunological synapse following agonist and antagonist stimulation. , 2002, Immunity.

[41]  Ronald N Germain,et al.  Modeling T Cell Antigen Discrimination Based on Feedback Control of Digital ERK Responses , 2005, PLoS biology.

[42]  S. Pierce,et al.  The initiation of antigen-induced B cell antigen receptor signaling viewed in living cells by fluorescence resonance energy transfer , 2005, Nature Immunology.

[43]  L. Samelson,et al.  Dynamic actin polymerization drives T cell receptor-induced spreading: a role for the signal transduction adaptor LAT. , 2001, Immunity.

[44]  Akihiro Kusumi,et al.  Paradigm shift of the plasma membrane concept from the two-dimensional continuum fluid to the partitioned fluid: high-speed single-molecule tracking of membrane molecules. , 2005, Annual review of biophysics and biomolecular structure.

[45]  O. Mandelboim,et al.  The human natural killer cell immune synapse. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[46]  T. McKeithan,et al.  Kinetic proofreading in T-cell receptor signal transduction. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Colin R. F. Monks,et al.  Three-dimensional segregation of supramolecular activation clusters in T cells , 1998, Nature.

[48]  I. Maly,et al.  Quantitative analysis of the role of receptor recycling in T cell polarization. , 2006, Biophysical journal.

[49]  J. Chauvin,et al.  Engagement of T cell receptor triggers its recruitment to low‐density detergent‐insoluble membrane domains , 1998, The EMBO journal.

[50]  G. Bhanot.  Results from modeling of B-Cell receptors binding to antigen. , 2004, Progress in biophysics and molecular biology.

[51]  K. Mossman,et al.  Altered TCR Signaling from Geometrically Repatterned Immunological Synapses , 2005, Science.

[52]  R. Sékaly,et al.  Triggering of T Cell Activation via CD4 Dimers1 , 2006, The Journal of Immunology.