Ca puffs underlie adhesion-triggered Ca microdomains in T cells.

Ca signalling is pivotal in T cell activation, an essential process in adaptive immune responses. Key to this activation are Ca microdomains, which are transient increases in cytosolic Ca concentration occurring within narrow regions between the endoplasmic reticulum (ER) and the plasma membrane (PM), lasting a few tens of milliseconds. Adhesion Dependent Ca Microdomains (ADCM) rely on store-operated Ca entry (SOCE) via the ORAI/STIM system. The nanometric scale at which these microdomains form poses challenges for direct experimental observation. Following the previous work of Gil et al. [1], which introduced a three-dimensional model of the ER-PM junction, this study combines a detailed description of the Ca fluxes at the junction with stochastic dynamics of a cluster of D-myo-inositol 1,4,5 trisphosphate receptors (IPR) located in the ER surrounding the junction. Because the consideration of Ca release through the IPR calls for the simulation of a portion of the cytoplasm considerably larger than the junction, our study also investigates the spatial distribution of PMCAs, revealing their likely localization outside the ER-PM junction. Simulations indicate that Ca puffs implying the opening of 2-6 IPRs create ADCMs by provoking local depletions of ER Ca stimulating Ca entry through the ORAI1 channels. Such conditions allow the reproduction of the amplitude, duration and spatial extent of the observed ADCMs. By integrating advanced computational techniques with insights from experimental studies, our approach provides valuable information on the mechanisms governing early Ca signalling in T cell activation, paving the way for a deeper understanding of immune responses.