作者
Alison F. Richard,Gordon L. Frazer,Y. Claire,Gillian M. Griffiths
摘要
Advances in optogenetic models, single-cell genomics, and live imaging allow new levels of precision in testing the impact of stimulation strength on T cell activation. Single cell studies have revealed that stimulation strength modulates the rate at which both naïve and effector T cells initiate fixed activation programs. Optogenetic experiments have shed light on the receptor–ligand binding requirements for T cell activation and effects of signaling duration on induced gene expression. Detailed examination of individual T cell receptor (TCR)–peptide MHC (pMHC) binding events suggest that activation-inducing interactions are rare and require a single long dwell time or sequential, spatially correlated binding events. A rate-limiting step in proximal T cell signaling has been identified in the slow modification of the LAT residue that recruits PLCy1, suggesting a means for controlling the probability of activation based on TCR–pMHC interaction times. How T lymphocytes tune their responses to different strengths of stimulation is a fundamental question in immunology. Recent work using new optogenetic, single-cell genomic, and live-imaging approaches has revealed that stimulation strength controls the rate of individual cell responses within a population. Moreover, these responses have been found to use shared molecular programs, regardless of stimulation strength. However, additional data indicate that stimulation duration or cytokine feedback can impact later gene expression phenotypes of activated cells. In-depth molecular studies have suggested mechanisms by which stimulation strength might modulate the probability of T cell activation. This emerging model allows activating T cells to achieve a wide range of population responses through probabilistic control within individual cells. How T lymphocytes tune their responses to different strengths of stimulation is a fundamental question in immunology. Recent work using new optogenetic, single-cell genomic, and live-imaging approaches has revealed that stimulation strength controls the rate of individual cell responses within a population. Moreover, these responses have been found to use shared molecular programs, regardless of stimulation strength. However, additional data indicate that stimulation duration or cytokine feedback can impact later gene expression phenotypes of activated cells. In-depth molecular studies have suggested mechanisms by which stimulation strength might modulate the probability of T cell activation. This emerging model allows activating T cells to achieve a wide range of population responses through probabilistic control within individual cells. here, a measurable molecular change downstream of TCR stimulation in an individual T cell that marks its commitment to an activation program. here, the number of T cells undergoing activation events per unit time. MHC-binding peptide in which individual amino acid residues of the cognate peptide are altered, changing the TCR–pMHC ligand interaction and, hence, the T cell stimulation strength. response occurs on a continuum. elevation of intracellular free [Ca2+]. artificial receptor designed to target a specific protein and induce signaling similar to that downstream of a TCR. activated T cell, secreting cytolytic components that elicit target cell death. While most of these are CD8+ effector T cells, CD4+ CTLs also exist. response is discrete, either seen or not seen, with no intermediary. time that a T cell contacts an APC, or TCR contacts pMHC. differentiated T cell providing a functional response. measurement of fluorescence intensity of individual cells, usually labeled with fluorescently bound antibodies, constructs, or dyes. specialized interface formed between immune cells and their partners (e.g., antigen-presenting cells) upon antigen recognition. mechanism for increasing ligand discrimination wherein the addition of reversible biochemical steps that delay the onset of further signaling enhances reliance of the pathway on receptor-ligand dwell time. multiprotein complex of proteins recruited to phosphorylated LAT. A T cell that has yet to encounter a TCR antigen that it recognizes in the periphery. introduction of light-sensitive proteins into cells to manipulate cellular behavior (e.g., the LOV2 photosensor domain from Avena sativa phototropin 1, or the phytochrome B–PhyB interacting factor ligand–receptor pair from Arabidopsis thaliana). peptide and MHC protein complex. opposite of a deterministic model; a mechanism whereby inputs affect the probability of an output being generated. For the rate-based model of stimulation strength impacting T cell activation, increasing the strength of stimulation increases the probability of signals surpassing a molecular threshold(s) within each individual cell. This changes the percentage of individual T cell–APC interactions that initiate activation per unit time, altering the population response. statistically inferred trajectory in which cells are ordered (and spaced) by the similarity of their molecular characteristics; when applied to cells undergoing a dynamic process, a trajectory constructed using a snapshot of heterogeneous cells at one real time point can be postulated to correspond to how a cell might progress through the process. integrated amount of activation-inducing signal a T cell senses through its TCR and other receptors sensing co-stimulation and the immune microenvironment. artificial lipid membrane bilayer supported on a planar surface (e.g., glass cover slips or chambers) and comprising the necessary protein components (e.g., fluorescent ICAM-1) to mediate cellular interactions subsequently visualized via microscopy.