Quantitative Network Signal Combinations Downstream of TCR Activation Can Predict IL2 Production Response1 (original) (raw)
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The Journal of Immunology, 2007
Proximal signaling events activated by TCR-peptide/MHC (TCR-pMHC) binding have been the focus of intense ongoing study, but understanding how the consequent downstream signaling networks integrate to govern ultimate avidity-appropriate TCR-pMHC T cell responses remains a crucial next challenge. We hypothesized that a quantitative combination of key downstream network signals across multiple pathways must encode the information generated by TCR activation, providing the basis for a quantitative model capable of interpreting and predicting T cell functional responses. To this end, we measured 11 protein nodes across six downstream pathways, along five time points from 10 min to 4 h, in a 1B6 T cell hybridoma stimulated by a set of three myelin proteolipid protein 139 -151 altered peptide ligands. A multivariate regression model generated from this data compendium successfully comprehends the various IL-2 production responses and moreover successfully predicts a priori the response to an additional peptide treatment, demonstrating that TCR binding information is quantitatively encoded in the downstream network. Individual node and/or time point measurements less effectively accounted for the IL-2 responses, indicating that signals must be integrated dynamically across multiple pathways to adequately represent the encoded TCR signaling information. Of further importance, the model also successfully predicted a priori direct experimental tests of the effects of individual and combined inhibitors of the MEK/ERK and PI3K/Akt pathways on this T cell response. Together, our findings show how multipathway network signals downstream of TCR activation quantitatively integrate to translate pMHC stimuli into functional cell responses.
Insights into the initiation of TCR signaling
Nature Immunology, 2014
The initiation of T cell antigen receptor signaling is a key step that can result in T cell activation and the orchestration of an adaptive immune response. Early events in T cell receptor signaling can distinguish between agonist and endogenous ligands with exquisite selectivity, and show extraordinary sensitivity to minute numbers of agonists in a sea of endogenous ligands. We review our current knowledge of models and crucial molecules that aim to provide a mechanistic explanation for these observations. Building on current understanding and a discussion of unresolved issues, we propose a molecular model for initiation of T cell receptor signaling that may serve as a useful guide for future studies.
TCR signalling network organization at the immunological synapses of murine regulatory T cells
European journal of immunology, 2017
Regulatory T (Treg) cells require T-cell receptor (TCR) signalling to exert their immunosuppressive activity, but the precise organization of the TCR signalling network compared to conventional T (Tconv) cells remains elusive. By using accurate mass spectrometry and multi-epitope ligand cartography (MELC) we characterized TCR signalling and recruitment of TCR signalling components to the immunological synapse (IS) in Treg cells and Tconv cells. With the exception of Themis which we detected in lower amounts in Treg cells, other major TCR signalling components were found equally abundant, however, their phosphorylation-status notably discriminates Treg cells from Tconv cells. Overall, this study identified 121 Treg cell-specific phosphorylations. Short-term triggering of T cell subsets via CD3 and CD28 widely harmonized these variations with the exception of eleven TCR signalling components that mainly regulate cytoskeleton dynamics and molecular transport. Accordingly, conjugation w...
Biophysical Journal, 2020
The adaptive immune response to a viral or bacterial infection involves T cells identifying and destroying infected cells. T cells have T cell receptors (TCRs) that bind specifically to their antigen in the form of a peptide bound to a major histocompatibility complex (pMHC) on the surface of an infected cell. The peptide bound in the pMHC molecule is revealing to the status of the cell; an infected cell presents a peptide fragment from a bacterial or viral protein whereas a healthy cell presents a self-peptide. The TCRs ability to distinguish and bind solely to peptides belonging to an infector is not well understood. To shed light on the mechanism of TCR recognition, we are performing binding simulations on a pMHC and TCR. Simulating the binding using traditional brute force methods would be computationally costly and might not even result in a binding event. To mitigate this, we are using a simulation package that implements a weighted ensemble approach called WESTPA. This method runs numerous simulations concurrently for short time periods. After each time period, there is a merging and replication algorithm that replicates interesting trajectories (ones moving towards the bound state) and combines uninteresting ones. The WESTPA simulation runs until there equilibrium is established between the bound and unbound populations. Weights of individual trajectories are calculated throughout the simulation and adjusted for merges and replications. We will characterize the WESTPA binding results in various ways, including first points of contact, the overall binding coordinate, and rate constants. The results of the binding simulation will allow us to gain a better understanding of the binding mechanism between the pMHC and TCR receptor and how the TCR invokes specificity.
Initiation of TCR signalling revisited
Trends in Immunology, 2003
T-cell receptor (TCR) multimerization has long been considered as an absolute prerequisite for T-cell activation. This view has been challenged by several recent reports showing that monomeric peptide-MHC (pMHC) complexes in solution could be stimulatory for T cells and that even a single pMHC at the immunological synapse was sufficient to trigger a T-cell Ca 21 response. Two incompatible models have been proposed to explain these new findings: the pseudodimer and the heterodimerization models. We consider that the heterodimerization model applied to adhesion-primed T cells provides an explanation for a larger set of experimental observations.
Journal of immunology (Baltimore, Md. : 1950), 1999
In the present study, we examined the relationships among quantitative aspects of TCR engagement as measured by receptor down-modulation, functional responses, and biochemical signaling events using both mouse and human T cell clones. For T cells from both species, ligands that are more potent in inducing functional responses promote TCR down-modulation more efficiently than weaker ligands. At low ligand density, the number of down-modulated TCR exceeds the number of available ligands by as much as 80-100:1 in the optimal human case, confirming the previous description of serial ligand engagement of TCR (Valitutti, et al. 1995. Nature 375:148-151). A previously unappreciated relationship involving TCR down-modulation, the pattern of proximal TCR signaling, and the extent of serial engagement was revealed by analyzing different ligands for the same TCR. Functionally, more potent ligands induce a higher proportion of fully tyrosine phosphorylated zeta-chains and a greater amount of ph...
T Cell Receptor Signaling Kinetics Takes the Stage
Science Signaling, 2010
It has been long surmised that the strength of stimulation of the T cell receptor (TCR) determines the robustness of TCR-mediated signaling and the magnitude of a T cell response. However, it is becoming evident that the signal from the TCR develops over time to approach its steady-state, affinity-determined maximal extent and that variations in this time have a substantial effect on the responsiveness of T cells. Here, I discuss data that show that the kinetics of signal propagation in various segments of the TCR signaling network can influence the spatiotemporal regulation of the effector functions of T cells and the quality of the T cell response. Proximal Signaling and Microcluster Formation Within a few seconds, engagement of the TCR initiates proximal signaling and the development of secondary TCR-mediated events that result in the formation of TCR signaling microclusters (1-3). These represent an essential membrane-associated platform for the development and maintenance of TCR signaling. Similar microclusters that contain proximal signaling proteins are formed in response to ligation of the B cell receptor (BCR) (4), which suggests that the concentration of signaling proteins at the sites of ligated antigen receptors is a general feature of the mechanism of lymphocyte activation.
Cellular-Level Versus Receptor-Level Response Threshold Hierarchies in T-Cell Activation
Frontiers in Immunology, 2013
Peptide-MHC (pMHC) ligand engagement by T-cell receptors (TCRs) elicits a variety of cellular responses, some of which require substantially more TCR-mediated stimulation than others.This threshold hierarchy could reside at the receptor level, where different response pathways branch off at different stages of the TCR/CD3 triggering cascade, or at the cellular level, where the cumulative TCR signal registered by the T-cell is compared to different threshold values. Alternatively, dual-level thresholds could exist. In this study, we show that the cellular hypothesis provides the most parsimonious explanation consistent with data obtained from an in-depth analysis of distinct functional responses elicited in a clonal T-cell system by a spectrum of biophysically defined altered peptide ligands across a range of concentrations. Further, we derive a mathematical model that describes how ligand density, affinity, and off-rate all affect signaling in distinct ways. However, under the kinetic regime prevailing in the experiments reported here, the TCR/pMHC class I (pMHCI) dissociation rate was found to be the main governing factor. The CD8 coreceptor modulated the TCR/pMHCI interaction and altered peptide ligand potency. Collectively, these findings elucidate the relationship between TCR/pMHCI kinetics and cellular function, thereby providing an integrated mechanistic understanding of T-cell response profiles.