Abstract
The adhesion zone of immune cells, the 'immunological synapse', exhibits characteristic domains of receptor–ligand complexes. The domain formation is probably caused by a length difference of the receptor–ligand complexes, and has been investigated in experiments in which T cells adhere to supported membranes with anchored ligands. For supported membranes with two types of anchored ligands, MHCp and ICAM1, which bind to the T-cell receptor (TCR) and the receptor LFA1 in the cell membrane, the coexistence of domains of the TCR–MHCp and LFA1–ICAM1 complexes in the cell adhesion zone has been observed for a wide range of ligand concentrations and affinities. For supported membranes with long and short ligands that bind to the same cell receptor CD2, in contrast, domain coexistence has been observed for a quite narrow ratio of ligand concentrations. In this paper, we determine detailed phase diagrams for cells adhering to supported membranes with a statistical–physical model of cell adhesion. We find a characteristic difference between the adhesion scenarios in which two types of ligands in a supported membrane bind (i) to the same cell receptor or (ii) to two different cell receptors, which helps us to explain the experimental observations. Our phase diagrams fully include thermal shape fluctuations of the cell membranes on nanometer scales, which lead to a critical point for the domain formation and to a cooperative binding of the receptors and ligands.
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GENERAL SCIENTIFIC SUMMARY Introduction and background. Cells adhere via the specific binding of a variety of receptor and ligand proteins that are anchored in the cell membranes. The adhesion of immune cells is often dominated by two types of bound receptor–ligand complexes with different lengths. The length difference causes elastic membrane deformations, which may lead to the segregation of the complexes and the formation of domains. Domain formation has been investigated in experiments in which immune cells adhere to planar supported membranes with anchored ligands that bind to cell receptors.
Main results. We present detailed phase diagrams for cells adhering to supported membranes via long and short receptor–ligand complexes. We find a qualitative difference between two experimentally investigated situations in which long and short ligands in the supported membrane bind (i) to the same cell receptor or (ii) to different cell receptors. The phase diagrams in the two situations resemble diagrams in the grand-canonical and the canonical ensemble, and result from different sizes of the reservoirs of unbound receptors in the cell membrane and unbound ligands in the supported membrane. The phase behavior is strongly affected by the deformations and thermal fluctuations of the elastic membranes.
Wider implications. The domain formation of receptor–ligand complexes during immune cell adhesion is a crucial step in the activation of immune responses. Our phase diagrams help to identify the conditions under which these domains are formed.
Figure. A cell adhering to a supported membrane with short (green) and long (red) ligands that bind to the same cell receptor. The length mismatch of the long and short receptor–ligand complexes leads to elastic membrane deformations and to an effective repulsion of the complexes.