Three-Dimensional Model of Sub-Plasmalemmal Ca2+ Microdomains Evoked by the Interplay Between ORAI1 and InsP3 Receptors
Diana Gil, Andreas H. Guse, Geneviève Dupont
Abstract
Ca 2+ signaling plays an essential role in T cell activation, which is a key step to start an adaptive immune response. During the transition from a quiescent to a fully activated state, Ca 2+ microdomains characterized by reduced spatial and temporal extents are observed in the junctions between the plasma membrane (PM) and the endoplasmic reticulum (ER). Such Ca 2+ responses can also occur in response to T cell adhesion to other cells or extracellular matrix proteins in otherwise unstimulated T cells. These non-TCR/CD3-dependent Ca 2+ microdomains rely on d - myo -inositol 1,4,5-trisphosphate (IP 3 ) signaling and subsequent store operated Ca 2+ entry (SOCE) via the ORAI/STIM system. The detailed molecular mechanism of adhesion-dependent Ca 2+ microdomain formation remains to be fully elucidated. We used mathematical modeling to investigate the spatiotemporal characteristics of T cell Ca 2+ microdomains and their molecular regulators. We developed a reaction-diffusion model using COMSOL Multiphysics to describe the evolution of cytosolic and ER Ca 2+ concentrations in a three-dimensional ER-PM junction. Equations are based on a previously proposed realistic description of the junction, which is extended to take into account IP 3 receptors (IP 3 R) that are located next to the junction. The first model only considered the ORAI channels and the SERCA pumps. Taking into account the existence of preformed clusters of ORAI1 and STIM2, ORAI1 slightly opens in conditions of a full ER. These simulated Ca 2+ microdomains are too small as compared to those observed in unstimulated T cells. When considering the opening of the IP 3 Rs located near the junction, the local depletion of ER Ca 2+ allows for larger Ca 2+ fluxes through the ORAI1 channels and hence larger local Ca 2+ concentrations. Computational results moreover show that Ca 2+ diffusion in the ER has a major impact on the Ca 2+ changes in the junction, by affecting the local Ca 2+ gradients in the sub-PM ER. Besides pointing out the likely involvement of the spontaneous openings of IP 3 Rs in the activation of SOCE in conditions of T cell adhesion prior to full activation, the model provides a tool to investigate how Ca 2+ microdomains extent and interact in response to T cell receptor activation.