Modeling T Cell Antigen Discrimination Based on Feedback Control of Digital ERK Responses

Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS Biology (Impact Factor: 9.34). 12/2005; 3(11):e356. DOI: 10.1371/journal.pbio.0030356
Source: PubMed


T-lymphocyte activation displays a remarkable combination of speed, sensitivity, and discrimination in response to peptide-major histocompatibility complex (pMHC) ligand engagement of clonally distributed antigen receptors (T cell receptors or TCRs). Even a few foreign pMHCs on the surface of an antigen-presenting cell trigger effective signaling within seconds, whereas 1 x 10(5)-1 x 10(6) self-pMHC ligands that may differ from the foreign stimulus by only a single amino acid fail to elicit this response. No existing model accounts for this nearly absolute distinction between closely related TCR ligands while also preserving the other canonical features of T-cell responses. Here we document the unexpected highly amplified and digital nature of extracellular signal-regulated kinase (ERK) activation in T cells. Based on this observation and evidence that competing positive- and negative-feedback loops contribute to TCR ligand discrimination, we constructed a new mathematical model of proximal TCR-dependent signaling. The model made clear that competition between a digital positive feedback based on ERK activity and an analog negative feedback involving SH2 domain-containing tyrosine phosphatase (SHP-1) was critical for defining a sharp ligand-discrimination threshold while preserving a rapid and sensitive response. Several nontrivial predictions of this model, including the notion that this threshold is highly sensitive to small changes in SHP-1 expression levels during cellular differentiation, were confirmed by experiment. These results combining computation and experiment reveal that ligand discrimination by T cells is controlled by the dynamics of competing feedback loops that regulate a high-gain digital amplifier, which is itself modulated during differentiation by alterations in the intracellular concentrations of key enzymes. The organization of the signaling network that we model here may be a prototypic solution to the problem of achieving ligand selectivity, low noise, and high sensitivity in biological responses.

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Available from: Grégoire Altan-Bonnet, Jan 06, 2014
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    • "> 0. If f ∝ τ n R +1 and g ∝ τ m+1 which is approximately the case for adaptive sorting (see above), we thus necessary have n R + 1 + β(m + 1) > 0, and thus for β = −1 we get n R > m . In many immune models [3] [5] [13] this constraint is naturally realized because the internal variable is regulated by a much earlier step (m) than the output (n R ) within the same proofreading cascade. "
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    ABSTRACT: Recent works in quantitative evolution have shown that biological structures are constrained by selected phenotypes in unexpected ways . This is also observed in simulations of gene network evolution, where complex realistic traits naturally appear even if they have not been explicitly selected . An important biological example is the absolute discrimination between different ligand "qualities", such as immune decisions based on binding times to T cell receptors (TCRs) or Fc$\epsilon$RIs. In evolutionary simulations, the phenomenon of absolute discrimination is not achieved without detrimental ligand antagonism: a "dog in the manger" effect in which ligands unable to trigger response prevent agonists to do so. A priori it seems paradoxical to improve ligand discrimination in a context of increased ligand antagonism, and how such contradictory phenotypes can be disentangled is unclear. Here we establish for the first time a direct mathematical causal link between absolute discrimination and ligand antagonism. Inspired by the famous discussion by Gould and Lewontin, we thus qualify antagonism as a "phenotypic spandrel": a phenotype existing as a necessary by-product of another phenotype. We exhibit a general model for absolute discrimination, and further show how addition of proofreading steps inverts the expected hierarchy of antagonism without fully cancelling it. Phenotypic spandrels reveal the internal feedbacks and constraints structuring response in signalling pathways, in very similar way to symmetries structuring physical laws.
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    • "The combination of the positive and the negative feedbacks, therefore, produces all or none response and balances the specificity and sensitivity . These results were experimentally confirmed by Altan- Bonnet's group in [37] [38]. "
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    ABSTRACT: Interaction only within specific molecules is a requisite for accurate operations of a biochemical reaction in a cell where bulk of background molecules exist. While structural specificity is a well-established mechanism for specific interaction, biophysical and biochemical experiments indicate that the mechanism is not sufficient for accounting for the antigen discrimination by T cells. In addition, the antigen discrimination by T cells also accompanies three intriguing properties other than the specificity: sensitivity, speed, and concentration compensation. In this work, we review experimental and theoretical works on the antigen discrimination by focusing on these four properties and show future directions towards understanding of the fundamental principle for molecular discrimination.
    BIOPHYSICS 01/2015; 11:85-92. DOI:10.2142/biophysics.11.85
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    • "Table S4 in File S2 includes citations of References [73], [74], [75], [76], [77], [78], [79]. Table S5 in File S2 includes citations of References [80], [81], [82], [83], [84], [85]. The Supplementary Text S1 (File S3) includes citations of References [86], [87], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [99], [100], [101], [102], [103], [104], [105], [106], [107], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124], [125], [126], [127], [128], [129], [130], [131], [132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145], [146], [147], [148], [149], [150], [151], [152], [153], [154], [155], [156], [157], [158], [159], [160], [161], [162], [163], [164], [165], [166], [167], [168], [169], [170], [171], [172], [173], [174], [175], [176], [177], [178], [179], [180], [181], [182], [183], [184], [185], [186], [187], [188], [189], [190], [191], [192], [193], [194], [195], [196], [197], [198], [199], [200], [201], [202], [203], [204], [205], [206], [207], [208], [209], [210], [211], [212], [213], [214], [215], [216], [217], [218], [219], [220], [221], [222]. "
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    ABSTRACT: In adaptive immune responses, T-cell receptor (TCR) signaling impacts multiple cellular processes and results in T-cell differentiation, proliferation, and cytokine production. Although individual protein-protein interactions and phosphorylation events have been studied extensively, we lack a systems-level understanding of how these components cooperate to control signaling dynamics, especially during the crucial first seconds of stimulation. Here, we used quantitative proteomics to characterize reshaping of the T-cell phosphoproteome in response to TCR/CD28 co-stimulation, and found that diverse dynamic patterns emerge within seconds. We detected phosphorylation dynamics as early as 5 s and observed widespread regulation of key TCR signaling proteins by 30 s. Development of a computational model pointed to the presence of novel regulatory mechanisms controlling phosphorylation of sites with central roles in TCR signaling. The model was used to generate predictions suggesting unexpected roles for the phosphatase PTPN6 (SHP-1) and shortcut recruitment of the actin regulator WAS. Predictions were validated experimentally. This integration of proteomics and modeling illustrates a novel, generalizable framework for solidifying quantitative understanding of a signaling network and for elucidating missing links.
    PLoS ONE 08/2014; 9(8):e104240. DOI:10.1371/journal.pone.0104240 · 3.23 Impact Factor
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