Spatiotemporal Regulation of Signaling: Focus on T Cell Activation and the Immunological Synapse

Abstract

In a signaling network, not only the functions of molecules are important but when (temporal) and where (spatial) those functions are exerted and orchestrated is what defines the signaling output. To temporally and spatially modulate signaling events, cells generate specialized functional domains with variable lifetime and size that concentrate signaling molecules, enhancing their transduction potential. The plasma membrane is a key in this regulation, as it constitutes a primary signaling hub that integrates signals within and across the membrane. Here, we examine some of the mechanisms that cells exhibit to spatiotemporally regulate signal transduction, focusing on the early events of T cell activation from triggering of T cell receptor to formation and maturation of the immunological synapse.

A computational study of co-inhibitory immune complex assembly at the interface between T cells and antigen presenting cells

“…As observed in previous experiments, co-regulatory receptors such as CTLA-4 and CD28 are spatially co-localized together with TCR/MHC complexes after the initial encounter of T cells with APC, leading into the assembly of signaling hubs called micro-clusters [ 17 ]. After further spreading of the T cell/APC interface, these micro-clusters merge together into a ring-like structure called central supramolecular activation cluster (cSMAC), as part of the immunological synapse [ 18 ]. Like many other systems of ligand-receptor complexes [ 19 ], formation of these spatial-temporal patterns at the interface between T cells and APC plays an essential role as the intercellular platform to regulate the dynamics of immune signaling pathways.…”

Dynamic Microtubule Arrays in Leukocytes and Their Role in Cell Migration and Immune Synapse Formation

“…Here we highlight the molecular basis of centrosome translocation and polarized vesicle secretion in T cells and antigen-presenting cells and the role of the microtubule cytoskeleton during these processes. We refer to excellent recent reviews, which discuss the signaling modules that regulate the repositioning of centrosomes toward the immune synapse ( Martín-Cófreces and Sánchez-Madrid, 2018 ; Garcia and Ismail, 2020 ; Tittarelli et al, 2020 ).…”

T-cell Receptor Is a Threshold Detector: Sub- and Supra-Threshold Stochastic Resonance in TCR-MHC Clusters on the Cell Surface

“…Both TCR and MHC stand in the front line of adaptive immunity in the initiating immune processes for defending the human body from foreign invaders, such as viruses [11]. During immune recognition, TCRs on the surface of a T cell are capable of very high efficiency scanning of the surface of the APC, whereby the presence of only a few pMHCs (1-10 peptides/APC) on the surface of the APC might be adequate for the successful activation of the T cell.…”

“…The initial contact of TCRs with pMHCs triggers a cascade on the surface of the T cell, leading to the formation of the immune synapse between the T cell and the APC, a junctional region resembling both in structure and function the synapse between nervous cells. However, in cross section, this junctional region is not homogeneous, with concentric circular regions called "central supramolecular activation cluster (SMAC)", (cSMAC), being in the middle, peripheral SMAC (pSMAC), circumventing the middle, and distal SMAC (dSMAC), circumventing the previous two [11]. During maturation of the synapse, TCRs move centripetally inward, from the "d" towards the "c" region, with their molecular neighbourhood signaling activity changing in parallel.…”