Abstract
Ca2+ signalling 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, Ca2+ microdomains of reduced spatial and temporal extents develop in the junctions between the plasma membrane and the endoplasmic reticulum (ER). These microdomains rely on Ca2+ entry from the extracellular medium, via the ORAI1/STIM1/STIM2 system that mediates store operated Ca2+ entry Store operated calcium entry. The mechanism leading to local store depletion and subsequent Ca2+ entry depends on the activation state of the cells. The initial, smaller microdomains are triggered by D-myo-inositol 1,4,5-trisphosphate (IP3) signalling in response to T cell adhesion. T cell receptor (TCR)/CD3 stimulation then initiates nicotinic acid adenine dinucleotide phosphate signalling, which activates ryanodine receptors (RYR). We have recently developed a mathematical model to elucidate the spatiotemporal Ca2+ dynamics of the microdomains triggered by IP3 signalling in response to T cell adhesion (Gil et al., 2021). This reaction-diffusion model describes the evolution of the cytosolic and endoplasmic reticulum Ca2+ concentrations in a three-dimensional ER-PM junction and was solved using COMSOL Multiphysics. Modelling predicted that adhesion-dependent microdomains result from the concerted activity of IP3 receptors and pre-formed ORAI1-STIM2 complexes. In the present study, we extend this model to include the role of RYRs rapidly after TCR/CD3 stimulation. The involvement of STIM1, which has a lower KD for Ca2+ than STIM2, is also considered. Detailed 3D spatio-temporal simulations show that these Ca2+ microdomains rely on the concerted opening of ∼7 RYRs that are simultaneously active in response to the increase in NAADP induced by T cell stimulation. Opening of these RYRs provoke a local depletion of ER Ca2+ that triggers Ca2+ flux through the ORAI1 channels. Simulations predict that RYRs are most probably located around the junction and that the increase in junctional Ca2+ concentration results from the combination between diffusion of Ca2+ released through the RYRs and Ca2+ entry through ORAI1 in the junction. The computational model moreover provides a tool allowing to investigate how Ca2+ microdomains occur, extend and interact in various states of T cell activation.
Highlights
Calcium signaling plays a crucial role in the activation of T cells and the adaptative immune response
Ca2+ Microdomains Simulated by the Opening of Type 1 Ryanodine Receptors Localized in the endoplasmic reticulum (ER)-PM Junction do Not Rely on ORAI1 Opening
It is known that ORAI1 and STIM are arranged in pre-formed complexes in the ER-PM junctions of T cells, the exact location of the RYR1s responsible for the decrease in [Ca2+]ER in the sub-PM ER remains to be determined
Summary
Calcium signaling plays a crucial role in the activation of T cells and the adaptative immune response. We took advantage of the great flexibility provided by computational modeling to investigate the respective roles played by the ER Ca2+ channels (IP3R or RYR) and the Ca2+ sensors (STIM1 and STIM2) in shaping the characteristics of the Ca2+ microdomains created by the openings of the related ORAI1 channels. This analysis allowed us to propose a unifying description of the molecular mechanism underlying T cells Ca2+ microdomains from adhesion to early TCR/CD3 stimulation. For further details regarding the system discretization and the use of COMSOL Multiphysics, please refer to the authors
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have