Differential Segregation in a Cell-Cell Contact Interface: The Dynamics of the Immunological Synapse

Abstract

Receptor-ligand couples in the cell-cell contact interface between a T cell and an antigen-presenting cell form distinct geometric patterns and undergo spatial rearrangement within the contact interface. Spatial segregation of the antigen and adhesion receptors occurs within seconds of contact, central aggregation of the antigen receptor then occurring over 1-5 min. This structure, called the immunological synapse, is becoming a paradigm for localized signaling. However, the mechanisms driving its formation, in particular spatial segregation, are currently not understood. With a reaction diffusion model incorporating thermodynamics, elasticity, and reaction kinetics, we examine the hypothesis that differing bond lengths (extracellular domain size) is the driving force behind molecular segregation. We derive two key conditions necessary for segregation: a thermodynamic criterion on the effective bond elasticity and a requirement for the seeding/nucleation of domains. Domains have a minimum length scale and will only spontaneously coalesce/aggregate if the contact area is small or the membrane relaxation distance large. Otherwise, differential attachment of receptors to the cytoskeleton is required for central aggregation. Our analysis indicates that differential bond lengths have a significant effect on synapse dynamics, i.e., there is a significant contribution to the free energy of the interaction, suggesting that segregation by differential bond length is important in cell-cell contact interfaces and the immunological synapse.

Simulations of the NK Cell Immune Synapse Reveal that Activation Thresholds Can Be Established by Inhibitory Receptors Acting Locally

“…When there are two bound molecules in neighboring positions, which differ in size of the extracellular domain by more than 10 nm, the membrane is assumed to be in stress, as has been suggested by previous models of the T cell IS (33,(44)(45)(46) and recently in experimental studies of NK cell synapses (47). To model the effect of the stress, the probability for the molecule to move away from the other molecule is multiplied by a stress factor.…”

The human CD94 gene encodes multiple, expressible transcripts including a new partner of NKG2A/B

“…31 These differences in the extracellular space between NK and target cells are probably determined by the size of pairs of receptor/ ligand interactions. 31,32 This pairing is likely due to thermodynamic processes that balance the optimization of local membrane separation against the entropy costs of segregation. This model would explain the spontaneous ATP-independent segregation of proteins observed at the iNKIS.…”

What is the importance of the immunological synapse?

“…Thus, supramolecular organization of some proteins can occur by mechanisms other than cytoskeletal or other ATP-dependent processes and perhaps micrometer-sized domains could be created by spontaneous segregation of receptors and ligands spanning similarly sized intercellular distances. The thermodynamics underlying this idea have been mathematically formulated by modelling the IS as consisting of apposing elastic membranes containing two differently sized receptor-ligand pairs [26,27]. It seems that the loss of entropy by segregation of proteins can be offset by the gain in energy from increased receptorligand interactions and minimising bending of the opposing membranes.…”