Equilibrium Thermodynamics of Cell-Cell Adhesion Mediated by Multiple Ligand-Receptor Pairs

Abstract

In many situations, cell-cell adhesion is mediated by multiple ligand-receptor pairs. For example, the interaction between T cells and antigen-presenting cells of the immune system is mediated not only by T cell receptors and their ligands (peptide-major histocompatibility complex) but also by binding of intracellular adhesion molecules. Interestingly, these binding pairs have different resting lengths. Fluorescent labeling reveals segregation of the longer adhesion molecules from the shorter T cell receptors in this case. Here, we explore the thermal equilibrium of a general cell-cell interaction mediated by two ligand-receptor pairs to examine competition between the elasticity of the cell wall, nonspecific intercellular repulsion, and bond formation, leading to segregation of bonds of different lengths at equilibrium. We make detailed predictions concerning the relationship between physical properties of the membrane and ligand-receptor pairs and equilibrium pattern formation, and suggest experiments to refine our understanding of the system. We demonstrate our model by application to the T cell/antigen-presenting-cell system and outline applications to natural killer cell adhesion.

Nanoscale Increases in CD2-CD48-mediated Intermembrane Spacing Decrease Adhesion and Reorganize the Immunological Synapse

“…Fig. 7 presents a hypothetical phase diagram of the type introduced by Goldstein and colleagues to discuss segregation in IS formation (35). This simplified schematic treats adhesion mediated by CD2 to CD48-WT or CD2 to CD48-CD22 interactions as yes or no phenomena with thresholds that are 10-fold lower for CD48-WT than for CD48-CD2 or CD48-CD22.…”

A Model for CD2/CD58-Mediated Adhesion Strengthening

“…Coombs et al only considered the TCR/pMHC interaction in the synapse, 6 while others considered all molecules involved and predicted the spatiotemporal evolution of the synapse. 3,5,17,22 In all these models, a constant contact area in the synapse was assumed. However, it has been shown experimentally that, when CD2-expressing Jurkat T lymphoblasts were allowed to settle on a CD58-incorporated lipid bilayer substrate, both CD2 and CD58 would accumulate in the contact area, which would increase simultaneously with the number of CD2 and CD58 molecules inside the contact area.…”

A Theoretical Framework for Quantitative Analysis of the Molecular Basis of Costimulation

“…Simulations have also revealed how the interplay of TCR/pMHC and LFA-1/ICAM-1 complex topologies and the mechanical properties of cytoskeleton-attached cell membranes could engender an intrinsic tendency for the receptor segregation characteristic of the mature immunological synapse (e.g., see Refs. [7][8][9][10][11]. Finally, in silico approaches have been used to support the concept that TCR signaling and degradation balance one another at the synapse (12).…”