Synaptic pattern formation during cellular recognition

Abstract

Important biological events, such as cell fate during development and initiation of various immune responses, are determined by binary cell-cell interactions. Much attention has been directed toward understanding the exquisitely specific molecular scale receptor-ligand binding that is essential for intercellular recognition and signaling. In many instances, successful engagement of a receptor with a complementary ligand on the apposing cell is, by itself, insufficient for sustained intracellular signaling and the concomitant triggering of a specific biological function. For example, the definitive event governing a mature immune response when T lymphocyte or natural killer (NK) cells interact with target cells is the formation of an immunological synapse (e.g., refs. 1-10). Concerted reorganization of the spatial pattern of membrane proteins and cell shape occurs during this recognition process (1-3). The resulting synapse is a clearly organized pattern of protein complexes, several microns in diameter, that forms at the junction between the membranes of the two cells. The mechanisms that drive the formation of synaptic patterns in intercellular junctions are not as well understood as the individual receptor-ligand binding events.Here, we examine whether the observed characteristics of synaptic patterns (1-3) can emerge spontaneously during cooperative interaction between populations of receptors and ligands in two apposed membranes. We consider a fluctuating twodimensional membrane containing proteins that can interact with a flat two-dimensional membrane containing complementary protein ligands (Fig. 1). An analogous configuration has been used (e.g., refs. 2, 7, and 10) to visualize synapse formation between T cells and supported lipid membranes. We formulate and study a model for this situation that explicitly incorporates protein binding and dissociation, lateral motion of proteins in the cell membranes, membrane mechanics (bending rigidity and tension), and protein down regulation. The results show that natural coupling of the forces due to these phenomena can lead to spatio-temporal evolution of protein patterns and cell shape resembling that observed during synapse formation in living cells. In this paper, we focus primarily on applying this general model to study the specialized junction between T cells and antigen-presenting cells (APC).The formation of functional immunological synapses between T cells and supported bilayers reconstituted to mimic APCs has recently been observed (2). A combination of interference reflection microscopy, fluorescence imaging, and immunoradiometric assays has provided quantitative information on the spatial pattern of membrane protein concentrations and membrane topography during synapse formation. Detailed accounts of these measurements and those with T cells and APCs (which exhibit the same phenomenology) are available (1, 2). Abbreviations: NK, natural killer; APC, antigen-presenting cell; ICAM-1, intercellular adhesion molecule-1; TCR, T cell antigen receptor; LFA-1, ...

Specific adhesion of membranes simultaneously supports dual heterogeneities in lipids and proteins

“…Theoretical models that combine protein reaction kinetics with the free energy of a fluid lipid membrane can lead to stable heterogeneities in protein distributions in the immunological synapse. 25,[37][38][39] Having binders of two different sizes was essential for these models to produce stable heterogeneities; binder size impacted the dependence of association kinetics on intermembrane distance and it gave rise to a membrane bending energy cost when unlike complexes were next to each other. These models did not incorporate heterogeneities in lipid distribution or phase.…”

NK cells from tuberculous pleurisy express high ICAM‐1 levels and exert stimulatory effect on local T cells

“…The surface enhancement of ICAM-1 on endothelial, APC and B cells have pleiotropic effects in LFA-1-mediated T lymphocyte responses including T-cell homing [25], formation and stabilization of immunosynapse [26,27], T-cell memory differentiation [28], and Th1 polarization [29,30], among others. However, little is known about ICAM-1/LFA-1 interaction in NK/T-cell cross-talk in physiological settings.…”

The Case for Absolute Ligand Discrimination: Modeling Information Processing and Decision by Immune T Cells

“…Understanding the forces associated with ligand-receptor interactions and the coupling with the mechanics of membrane deformation would be critical to account for the differential potency of ligands to activate T cells. Such quantitative models have been introduced [53], based on Ginzburg-Landau equations coupling the biochemistry of ligand-receptor interactions with the energetic cost of membrane deformation. Such models established that biochemical/mechanical coupling could be sufficient to physically sort membrane proteins on the T:APC cell interface, and generate a threshold of activation.…”