scholarly journals Understanding the Dynamics of T-Cell Activation in Health and Disease Through the Lens of Computational Modeling

2019 ◽  
pp. 1-8 ◽  
Author(s):  
Jennifer A. Rohrs ◽  
Pin Wang ◽  
Stacey D. Finley
Keyword(s):  
T Cell ◽  
Computational Modeling ◽  
T Cell Activation ◽  
Intracellular Signaling ◽  
Rational Design ◽  
Cell Activation ◽  
Computational Models ◽  
Mechanistic Models ◽  
Design And Optimization ◽  
Endogenous Proteins

T cells in the immune system are activated by binding to foreign peptides (from an external pathogen) or mutant peptide (derived from endogenous proteins) displayed on the surface of a diseased cell. This triggers a series of intracellular signaling pathways, which ultimately dictate the response of the T cell. The insights from computational models have greatly improved our understanding of the mechanisms that control T-cell activation. In this review, we focus on the use of ordinary differential equation–based mechanistic models to study T-cell activation. We highlight several examples that demonstrate the models’ utility in answering specific questions related to T-cell activation signaling, from antigen discrimination to the feedback mechanisms that initiate transcription factor activation. In addition, we describe other modeling approaches that can be combined with mechanistic models to bridge time scales and better understand how intracellular signaling events, which occur on the order of seconds to minutes, influence phenotypic responses of T-cell activation, which occur on the order of hours to days. Overall, through concrete examples, we emphasize how computational modeling can be used to enable the rational design and optimization of immunotherapies.

scholarly journals T cell receptor zeta/CD3-p59fyn(T)-associated p120/130 binds to the SH2 domain of p59fyn(T).

1993 ◽  
Vol 178 (6) ◽  
pp. 2107-2113 ◽  
Author(s):  
A J da Silva ◽  
O Janssen ◽  
C E Rudd
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Intracellular Signaling ◽  
Cell Activation ◽  
Cell Receptor ◽  
Sh2 Domain ◽  
T Complex

Intracellular signaling from the T cell receptor (TCR)zeta/CD3 complex is likely to be mediated by associated protein tyrosine kinases such as p59fyn(T), ZAP-70, and the CD4:p56lck and CD8:p56lck coreceptors. The nature of the signaling cascade initiated by these kinases, their specificities, and downstream targets remain to be elucidated. The TCR-zeta/CD3:p59fyn(T) complex has previously been noted to coprecipitate a 120/130-kD doublet (p120/130). This intracellular protein of unknown identity associates directly with p59fyn(T) within the receptor complex. In this study, we have shown that this interaction with p120/130 is specifically mediated by the SH2 domain (not the fyn-SH3 domain) of p59fyn(T). Further, based on the results of in vitro kinase assays, p120/130 appears to be preferentially associated with p59fyn(T) in T cells, and not with p56lck. Antibody reprecipitation studies identified p120/130 as a previously described 130-kD substrate of pp60v-src whose function and structure is unknown. TCR-zeta/CD3 induced activation of T cells augmented the tyrosine phosphorylation of p120/130 in vivo as detected by antibody and GST:fyn-SH2 fusion proteins. p120/130 represents the first identified p59fyn(T):SH2 binding substrate in T cells, and as such is likely to play a key role in the early events of T cell activation.

scholarly journals Evidence for differential intracellular signaling via CD4 and CD8 molecules.

1994 ◽  
Vol 179 (2) ◽  
pp. 727-732 ◽  
Author(s):  
K S Ravichandran ◽  
S J Burakoff
Keyword(s):  
Protein Kinase C ◽  
T Cell ◽  
Protein Kinase ◽  
T Cell Activation ◽  
Intracellular Signaling ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Kinase Assay ◽  
Cross Linking ◽  
Kinase C

Although both the CD4 and CD8 molecules enhance antigen responsiveness mediated by the T cell receptor (TCR), it is not known whether CD4 and CD8 initiate similar or different intracellular signals when they act as coreceptors. To characterize the early signals transmitted by CD4 and CD8, both CD4 and CD8 alpha were expressed in the same murine T cell hybridoma. In the double positive transfectants, CD4 and CD8 associated with equal amounts of p56lck (Lck), and both molecules enhanced interleukin 2 (IL-2) production equivalently when cross-linked with suboptimal levels of anti-TCR antibody. However, in an in vitro kinase assay, cross-linking CD4 initiated fourfold greater kinase activity compared with CD8 cross-linking. In the same assay, when CD4 or CD8 was cross-linked to the TCR, novel phosphorylated proteins were found associated with the TCR/CD4 complex but not with the TCR/CD8 complex. Consistent with this data, antiphosphotyrosine immunoblotting revealed greater tyrosine phosphorylation of intracellular substrates after TCR/CD4 cross-linking compared with TCR/CD8 cross-linking. Additionally, a specific protein kinase C inhibitor (RO318220) inhibited CD8-mediated enhancement of IL-2 production far more effectively than CD4-mediated enhancement. Thus, it appears that CD8 alpha may depend more on a protein kinase C-mediated signaling pathway, whereas CD4 may rely on greater tyrosine kinase activation. Such differential signaling via CD4 and CD8 has implications for thymic ontogeny and T cell activation.

How many dendritic cells are required to initiate a T-cell response?

Blood ◽  
2012 ◽  
Vol 120 (19) ◽  
pp. 3945-3948 ◽  
Author(s):  
Susanna Celli ◽  
Mark Day ◽  
Andreas J. Müller ◽  
Carmen Molina-Paris ◽  
Grant Lythe ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
T Cell Activation ◽  
Cell Response ◽  
Rational Design ◽  
Cell Activation ◽  
T Cell Response ◽  
Cell Responses ◽  
Precursor Frequency

Abstract T-cell activation in lymph nodes relies on encounters with antigen (Ag)–bearing dendritic cells (DCs) but the number of DCs required to initiate an immune response is unknown. Here we have used a combination of flow cytometry, 2-photon imaging, and computational modeling to quantify the probability of T cell–DC encounters. We calculated that the chance for a T cell residing 24 hours in a murine popliteal lymph nodes to interact with a DC was 8%, 58%, and 99% in the presence of 10, 100, and 1000 Ag-bearing DCs, respectively. Our results reveal the existence of a threshold in DC numbers below which T-cell responses fail to be elicited for probabilistic reasons. In mice and probably humans, we estimate that a minimum of 85 DCs are required to initiate a T-cell response when starting from precursor frequency of 10−6. Our results have implications for the rational design of DC-based vaccines.

scholarly journals The structural basis of T-cell receptor (TCR) activation: An enduring enigma

2019 ◽  
Vol 295 (4) ◽  
pp. 914-925 ◽  
Author(s):  
Roy A. Mariuzza ◽  
Pragati Agnihotri ◽  
John Orban
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Intracellular Signaling ◽  
Rational Design ◽  
Cell Receptor ◽  
Structural Basis ◽  
Specific Information ◽  
Antigenic Peptides ◽  
Tcr Activation

T cells are critical for protective immune responses to pathogens and tumors. The T-cell receptor (TCR)–CD3 complex is composed of a diverse αβ TCR heterodimer noncovalently associated with the invariant CD3 dimers CD3ϵγ, CD3ϵδ, and CD3ζζ. The TCR mediates recognition of antigenic peptides bound to MHC molecules (pMHC), whereas the CD3 molecules transduce activation signals to the T cell. Whereas much is known about downstream T-cell signaling pathways, the mechanism whereby TCR engagement by pMHC is first communicated to the CD3 signaling apparatus, a process termed early T-cell activation, remains largely a mystery. In this review, we examine the molecular basis for TCR activation in light of the recently determined cryoEM structure of a complete TCR–CD3 complex. This structure provides an unprecedented opportunity to assess various signaling models that have been proposed for the TCR. We review evidence from single-molecule and structural studies for force-induced conformational changes in the TCR–CD3 complex, for dynamically-driven TCR allostery, and for pMHC-induced structural changes in the transmembrane and cytoplasmic regions of CD3 subunits. We identify major knowledge gaps that must be filled in order to arrive at a comprehensive model of TCR activation that explains, at the molecular level, how pMHC-specific information is transmitted across the T-cell membrane to initiate intracellular signaling. An in-depth understanding of this process will accelerate the rational design of immunotherapeutic agents targeting the TCR–CD3 complex.

scholarly journals Farnesyltransferase inhibitors inhibit T-cell cytokine production at the posttranscriptional level

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 1982-1988 ◽  
Author(s):  
Reinhard E. Marks ◽  
Allen W. Ho ◽  
Christian Robbel ◽  
Todd Kuna ◽  
Seth Berk ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Intracellular Signaling ◽  
Map Kinases ◽  
Cell Activation ◽  
Cytokine Production ◽  
Immunosuppressive Agents ◽  
Farnesyltransferase Inhibitors ◽  
Human T Cell ◽  
Posttranscriptional Level

Abstract Several cytoplasmic proteins, such as GTPases of the Ras family, containing a C-terminal CAAX motif are prenylated by farnesyltransferase to facilitate localization to cellular membranes where activation occurs. Farnesyltransferase inhibitors (FTIs) interfere with this farnesylation process, thereby preventing proper membrane localization and rendering the proteins unavailable for activation. Currently, FTIs are being explored as antineoplastic agents for the treatment of several malignancies. However, since farnesylated proteins like Ras are also involved in intracellular signaling in lymphocytes, FTIs might interfere with T-cell activation. Based on this hypothesis we examined the effect of several FTIs on cytokine production in response to anti-CD3 + anti-CD28 monoclonal antibodies or PMA + ionomycin. Murine Th1 and Th2 clones, stimulated in the presence of FTIs, showed a dose-dependent reduction of lineage-specific cytokine secretion (IFN-γ, IL-2, IL-4, IL-5). However, no inhibition of ERK or JNK MAP kinases was observed, nor was induction of cytokine mRNA affected. Rather, intracellular cytokine protein synthesis was blocked. Inhibition of human T-cell INF-γ production also was observed, correlating with reduced phosphorylation of p70S6K. These results indicate that FTIs inhibit T-cell activation at the posttranscriptional level and also suggest that they may have potential as novel immunosuppressive agents.

scholarly journals Sts-2 Is a Phosphatase That Negatively Regulates Zeta-associated Protein (ZAP)-70 and T Cell Receptor Signaling Pathways

2011 ◽  
Vol 286 (18) ◽  
pp. 15943-15954 ◽  
Author(s):  
Boris San Luis ◽  
Ben Sondgeroth ◽  
Nicolas Nassar ◽  
Nick Carpino
Keyword(s):  
T Cell ◽  
Signaling Pathways ◽  
Phosphatase Activity ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Intracellular Signaling ◽  
Cell Activation ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Homologous Proteins

T cell activity is controlled in large part by the T cell receptor (TCR). The TCR detects the presence of foreign pathogens and activates the T cell-mediated immune reaction. Numerous intracellular signaling pathways downstream of the TCR are involved in the process of T cell activation. Negative regulation of these pathways helps prevent excessive and deleterious T cell responses. Two homologous proteins, Sts-1 and Sts-2, have been shown to function as critical negative regulators of TCR signaling. The phosphoglycerate mutase-like domain of Sts-1 (Sts-1PGM) has a potent phosphatase activity that contributes to the suppression of TCR signaling. The function of Sts-2PGM as a phosphatase has been less clear, principally because its intrinsic enzyme activity has been difficult to detect. Here, we demonstrate that Sts-2 regulates the level of tyrosine phosphorylation on targets within T cells, among them the critical T cell tyrosine kinase Zap-70. Utilizing new phosphorylated substrates, we demonstrate that Sts-2PGM has clear, albeit weak, phosphatase activity. We further pinpoint Sts-2 residues Glu-481, Ser-552, and Ser-582 as specificity determinants, in that an Sts-2PGM triple mutant in which these three amino acids are altered to their counterparts in Sts-1PGM has substantially increased activity. Our results suggest that the phosphatase activities of both suppressor of TCR signaling homologues cooperate in a similar but independent fashion to help set the threshold for TCR-induced T cell activation.

scholarly journals T cell activation and immune synapse organization respond to the microscale mechanics of structured surfaces

2019 ◽  
Vol 116 (40) ◽  
pp. 19835-19840 ◽  
Author(s):  
Weiyang Jin ◽  
Fella Tamzalit ◽  
Parthiv Kant Chaudhuri ◽  
Charles T. Black ◽  
Morgan Huse ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Intracellular Signaling ◽  
Cell Activation ◽  
Multiple Scales ◽  
Adaptive Immune Response ◽  
Mechanical Stiffness ◽  
Form Complex ◽  
Structured Surfaces

Cells have the remarkable ability to sense the mechanical stiffness of their surroundings. This has been studied extensively in the context of cells interacting with planar surfaces, a conceptually elegant model that also has application in biomaterial design. However, physiological interfaces are spatially complex, exhibiting topographical features that are described over multiple scales. This report explores mechanosensing of microstructured elastomer surfaces by CD4+ T cells, key mediators of the adaptive immune response. We show that T cells form complex interactions with elastomer micropillar arrays, extending processes into spaces between structures and forming local areas of contraction and expansion dictated by the layout of microtubules within this interface. Conversely, cytoskeletal reorganization and intracellular signaling are sensitive to the pillar dimensions and flexibility. Unexpectedly, these measures show different responses to substrate rigidity, suggesting competing processes in overall T cell mechanosensing. The results of this study demonstrate that T cells sense the local rigidity of their environment, leading to strategies for biomaterial design.

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