In silico characterization of mechanisms positioning costimulatory and checkpoint complexes in immune synapses

Abstract

Integrin and small immunoglobulin superfamily (sIGSF) adhesion complexes function physiologically in human immunological synapses (IS) wherein sIGSF complexes form a corolla of microdomains around an integrin ring and secretory core. The corolla recruits and retains the major costimulatory and checkpoint complexes that regulate the response to T cell receptor (TCR) engagement, making forces that govern corolla formation of particular interest. We developed a phenomenological agent-based model in order to test different hypotheses concerning the mechanisms underlying molecular reorganization during IS formation. The model showed that sIGSF complexes are passively excluded to the distal aspect of the IS as long as their interaction with the ramified F-actin transport network is absent or weaker than that of integrins. An attractive force between sIGSF adhesion and costimulatory/checkpoint complexes relocates the latter from the centre of the IS to the corolla. The simulations suggest that size based sorting interactions with large glycocalyx components as well as a short-range self-attraction between sIGSF complexes explain the corolla "petals". These molecular and mechanistic features establish a general model that can recapitulate complex pattern formation processes observed in cell-bilayer and cell-cell interfaces. One Sentence SummaryComputer simulations of immunological synapses reveal the localization mechanisms of immunoglobulin superfamily adhesion and costimulatory/checkpoint complexes.