T cell sensitivity and specificity - kinetic proofreading revisited

Chan, CP; George, Andrew; Stark, Jaroslav

doi:10.3934/dcdsb.2003.3.343

Cited by 34 publications

(56 citation statements)

References 34 publications

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“…The models also show that, although this long delay preferentially reduces TCR signaling for larger off‐rates, it reduces TCR signaling at all off‐rates. This means that improving specificity comes at a cost to sensitivity . A quantitative analysis suggested that there is no parameter regime where the standard kinetic proofreading model can explain the observed discrimination …”

Section: Relationship Between Antigen Sensitivity and Specificitymentioning

confidence: 99%

Molecular mechanisms of T cell sensitivity to antigen

Siller-Farfán

Dushek

2018

Immunological Reviews

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T cells initiate and regulate adaptive immune responses that can clear infections. To do this, they use their T cell receptors (TCRs) to continually scan the surfaces of other cells for cognate peptide antigens presented on major histocompatibility complexes (pMHCs). Experimental work has established that as few 1-10 pMHCs are sufficient to activate T cells. This sensitivity is remarkable in light of a number of factors, including the observation that the TCR and pMHC are short molecules relative to highly abundant long surface molecules, such as CD45, that can hinder initial binding, and moreover, the TCR/pMHC interaction is of weak affinity with solution lifetimes of approximately 1 second. Here, we review experimental and mathematical work that has contributed to uncovering molecular mechanisms of T cell sensitivity. We organize the mechanisms by where they act in the pathway to activate T cells, namely mechanisms that (a) promote TCR/pMHC binding, (b) induce rapid TCR signaling, and (c) amplify TCR signaling. We discuss work showing that high sensitivity reduces antigen specificity unless molecular feedbacks are invoked. We conclude by summarizing a number of open questions.

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Section: Relationship Between Antigen Sensitivity and Specificitymentioning

confidence: 99%

Molecular mechanisms of T cell sensitivity to antigen

Siller-Farfán

Dushek

2018

Immunological Reviews

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“…(iii) Reversal of these modifications is quick in that the receptor is always in the basal (unactivated) state when it binds a pMHC. Consistent with the predictions of this model, Kersh et al [37] found that pMHC with different half-lives of binding to TCR generate different phosphorylated forms of CD3-, a molecule that associates with TCR as part of the signaling complex (although the details of this consistency have been challenged [8]).…”

Section: Kinetic Proofreadingmentioning

confidence: 68%

“…A recent reanalysis of kinetic proofreading [8] explicitly quantified the concepts of sensitivity and specificity using the notions of true and false signaling events and true and false negative (lack of signaling) events. Using TP, FP, TN and FN to describe these events, the standard definitions are sensitivity = TP/(TP + FN) and specificity = TP/(TP + FP).…”

Section: Limitations Of Kinetic Proofreadingmentioning

confidence: 99%

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T cell activation: Kinetic proofreading, serial engagement and cell adhesion

Coombs

Goldstein

2005

Journal of Computational and Applied Mathematics

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There is a fundamental difference in complexity between signaling initiated by ligands on the surface of one cell binding to receptors on the surface of another cell and ligands in solution binding to these receptors. The fact that two cells must approach each other and form a number of intercellular bonds of different types, all within the restricted geometry of the intercellular contact region, introduces the possibility of complex spatio-temporal dynamics of surface receptors that is not present otherwise. Mathematical modelling of these dynamics is in its early stages. However, useful tools have emerged. The purpose of this paper is to describe some of these mathematical tools, indicating their strengths and shortcomings, and suggest some directions for future theoretical studies.

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“…Although T-cell activation has been a fertile area for mathematical modeling there have been very few studies that include system stochasticity (15)(16)(17)(18)(19), and none that have explored the consequences of low agonist density on signaling characteristics. Conceptually, kinetic proofreading has been a key platform on which to discuss specificity (20,21), although this was recently criticized for being insufficiently sensitive at high specificity (22). Despite these and other T-cell activation models, theoretically it remains unclear how complex TCR triggering dynamics must be to filter out self-peptide noise while achieving high sensitivity, and further, the circuit architecture that is required, e.g., strength of nonlinear feedback (23,24), filtering, or amplification steps.…”

Section: Introductionmentioning

confidence: 99%

T-Cell Activation: A Queuing Theory Analysis at Low Agonist Density

Wedagedera

Burroughs

2006

Biophysical Journal

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We analyze a simple linear triggering model of the T-cell receptor (TCR) within the framework of queuing theory, in which TCRs enter the queue upon full activation and exit by downregulation. We fit our model to four experimentally characterized threshold activation criteria and analyze their specificity and sensitivity: the initial calcium spike, cytotoxicity, immunological synapse formation, and cytokine secretion. Specificity characteristics improve as the time window for detection increases, saturating for time periods on the timescale of downregulation; thus, the calcium spike (30 s) has low specificity but a sensitivity to single-peptide MHC ligands, while the cytokine threshold (1 h) can distinguish ligands with a 30% variation in the complex lifetime. However, a robustness analysis shows that these properties are degraded when the queue parameters are subject to variation-for example, under stochasticity in the ligand number in the cell-cell interface and population variation in the cellular threshold. A time integration of the queue over a period of hours is shown to be able to control parameter noise efficiently for realistic parameter values when integrated over sufficiently long time periods (hours), the discrimination characteristics being determined by the TCR signal cascade kinetics (a kinetic proofreading scheme). Therefore, through a combination of thresholds and signal integration, a T cell can be responsive to low ligand density and specific to agonist quality. We suggest that multiple threshold mechanisms are employed to establish the conditions for efficient signal integration, i.e., coordinate the formation of a stable contact interface.

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T cell sensitivity and specificity - kinetic proofreading revisited

Cited by 34 publications

References 34 publications

Molecular mechanisms of T cell sensitivity to antigen

Molecular mechanisms of T cell sensitivity to antigen

T cell activation: Kinetic proofreading, serial engagement and cell adhesion

T-Cell Activation: A Queuing Theory Analysis at Low Agonist Density

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