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

Area of Science:

• Immunology
• Computational Biology
• Cell Biology

Background:

• Mechanisms distinguishing self- from foreign antigens before T cell activation remain unclear.
• Antigen-presenting cells (APCs) and T cells form molecular complexes during adaptive immune responses.
• CTLA4 expression on T cells modulates T cell activation, and the CTLA4 transendocytosis hypothesis proposes its role in depleting APC co-stimulatory molecules.

Purpose of the Study:

• To develop and utilize a multiscale spatiotemporal model to investigate the dynamics of T cell-APC interactions.
• To test the CTLA4 transendocytosis hypothesis by simulating the depletion of CD80 and CD86 proteins from APC membranes.
• To elucidate the timescales and molecular processes governing immune complex formation and T cell activation.

Main Methods:

• Development of a multiscale spatiotemporal computational model simulating T cell-APC interactions.
• Modeling the formation of transmembrane complexes (MHC-TCR and CD80/CD86-CD28) and concentration gradients of membrane proteins.
• Simulating protein diffusion, complexation, internalization, and degradation over timescales spanning five orders of magnitude.

Main Results:

• Simulated concentration gradients of free membrane proteins reached maximums within seconds and equalized over hours.
• CTLA4 expression and complexation with CD80/CD86 led to the internalization and degradation of these co-stimulatory molecules.
• Model results demonstrated agreement with experimental data, highlighting the broad timescale of molecular processes.

Conclusions:

• The study's findings are consistent with the CTLA4 transendocytosis hypothesis.
• Lateral diffusion of surface proteins and geometrical constraints significantly influence the kinetics of immune synapse formation.
• The model underscores the importance of diffusion-limited processes in regulating T cell activation signals over extended periods.