Abstract
During immunological synapse (IS) formation, Tcell 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 Tcell activation and fate decisions.
Highlights
The formation of immune synapses (ISs) is a central process for antigen recognition by T cells
Initial Model for IS Formation In order to understand the mechanisms driving spatial organization of molecules in the IS, we start from an agent-based model taking into account T cell receptor (TCR), leukocyte-functionassociated antigen 1 (LFA-1), peptide-bound major histocompatibility complexes (pMHC), and intracellular activation molecule 1 (ICAM-1) only
Free molecules may bind to their cognate ligand on the opposite lattice and already formed complexes can return to the free-molecule state according to their respective dissociation constants (Table 1; Figge and Meyer-Hermann, 2009)
Summary
Siokis et al analyze the impact of actinderived forces on the positioning of molecules during immunological synapse formation. While CD28 can reach the center of the synapse by passively following TCR microclusters, the characteristic ring-like pattern of CD28 complexes requires coupling to actin. 2018, Cell Reports 24, 1151–1162 July 31, 2018 a 2018 The Author(s).
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