Multiscale Modeling of Complex Formation and CD80 Depletion during Immune Synapse Development.

The mechanisms that discriminate self- and foreign antigen before T cell activation are unresolved. As part of the immune system's adaptive response to specific infections or neoplasms, antigen-presenting cells (APC) and effector T cells form transcellular molecular complexes. CTLA4 expression on regulatory or effector T cells reduces T cell activation. The CTLA4 transendocytosis hypothesis proposes that CTLA4 depletes CD80 and CD86 proteins from the APC membrane, rendering the APC incapable of activating T cells. We developed a multiscale spatiotemporal model for the interaction of a T cell and APC. Formation of the immune complex between T cell and APC starts with formation of the transmembrane complexes between the major histocompatibility complex and the T cell receptor (Signal 1) and between CD80 or CD86 and CD28 (Signal 2) at the opposing membrane surfaces of the interacting cells. By 0.01 s after contact simulation, an increasing concentration gradient of the free membrane proteins develops between the opposing surfaces and spherical parts of each cell's membrane, reaching a maximum at ∼30 s. Over several hours, diffusion across the gradient equalizes the free protein concentrations. During this phase, CTLA4 surface expression and its complexation with CD80/CD86 cause internalization and degradation of CD80/CD86. The simulation results show reasonable agreement with reported experimental data and indicate that key molecular processes take place over a very broad timescale, covering five orders of magnitude. Besides the fast complexation reactions, diffusion-limited processes, especially lateral diffusion in cell membranes and geometrical constraints, considerably slow down evolution of the synapse. Our results are consistent with the CTLA4 transendocytosis hypothesis and suggest the importance of lateral diffusion of surface proteins in contributing to a gradual increase in Signal 1 and Signal 2.