F-Actin-Driven CD28-CD80 Localization in the Immune Synapse

Authored by Michael Meyer-Hermann, Anastasios Siokis, Philippe A Robert, Philippos Demetriou, Michael L Dustin

Date Published: 2018

DOI: 10.1016/j.celrep.2018.06.114

Sponsors: Wellcome Trust Human Frontier Science Program Kennedy Trust for Rheumatology Research

Platforms: C++

Model Documentation: Other Narrative

Model Code URLs: Model code not found

Abstract

During immunological synapse (IS) formation, T cell receptor (TCR) signaling complexes, integrins, and costimulatory molecules exhibit a particular spatial localization. Here, we develop an agent-based model for the IS formation based on TCR peptide-bound major histocompatibility complex (pMHC) and leukocyte-function-associated antigen 1 (LFA-1) intracellular activation molecule 1 (ICAM-1) dynamics, including CD28 binding to a costimulatory ligand, coupling of molecules to the centripetal actin flow, and size-based segregation (SBS). A radial gradient of LFA-1 in the peripheral supramolecular activation cluster (pSMAC) toward the central supramolecular activation cluster (cSMAC) emerged as a combined consequence of actin binding and diffusion and modified the positioning of other molecules. The simulations predict a mechanism of CD28 movement, according to which CD28-CD80 complexes passively follow TCR-pMHC microclusters. However, the characteristic CD28-CD80 localization in a ring pattern around the cSMAC only emerges with a particular CD28-actin coupling strength that induces a centripetal motion. These results have implications for the understanding of T cell activation and fate decisions.

Tags

Monte-carlo-simulation Pattern-formation T-cell-activation Kinase-c-theta Immunological synapse Tcr-cd28 microclusters Retrograde flow Filamin-a Cd28 Ctla-4