Publications about 'T cells'
Articles in journal or book chapters
  1. N. Trendel, P. Kruger, S. Gaglione, J. Nguyen, J. Pettmann, E.D. Sontag, and O. Dushek. Perfect adaptation of CD8+ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation. Science Signaling, 14:eaay9363, 2021. [PDF] Keyword(s): immunology, cell signaling, T cells, systems biology.
    Maintaining and limiting T cell responses to constant antigen stimulation is critical to control pathogens and maintain self-tolerance, respectively. Antigen recognition by T cell receptors (TCRs) induces signalling that activates T cells to produce cytokines and also leads to the downregulation of surface TCRs. In other systems, receptor downregulation can induce perfect adaptation to constant stimulation by a mechanism known as state-dependent inactivation that requires complete downregulation of the receptor or the ligand. However, this is not the case for the TCR, and therefore, precisely how TCR downregulation maintains or limits T cell responses is controversial. Here, we observed that in vitro expanded primary human T cells exhibit perfect adaptation in cytokine production to constant antigen stimulation across a 100,000-fold variation in affinity with partial TCR downregulation. By directly fitting a mechanistic model to the data, we show that TCR downregulation produces imperfect adaptation, but when coupled to a switch produces perfect adaptation in cytokine production. A pre diction of the model is that pMHC-induced TCR signalling continues after adaptation and this is confirmed by showing that, while costimulation cannot prevent adaptation, CD28 and 4-1BB signalling reactivated adapted T cells to produce cytokines in a pMHC-dependent manner. We show that adaptation also applied to 1st generation chimeric antigen receptor (CAR)-T cells but is partially avoided in 2nd generation CARs. These findings highlight that even partial TCR downregulation can limit T cell responses by producing perfect adaptation rendering T cells dependent on costimulation for sustained responses.

  2. E.V. Nikolaev, A. Zloza, and E.D. Sontag. Immunobiochemical reconstruction of influenza lung infection - melanoma skin cancer interactions. Frontiers in Immunology, 10:Article 4, 2019. [PDF] Keyword(s): oncology, cancer, infections, immunology, checkpoint inhibition, systems biology.
    Recent experimental results from the Zloza lab combined a mouse model of influenza A virus (IAV) infection (A/H1N1/PR8) and a highly aggressive model of infection-unrelated cancer, B16-F10 skin melanoma. This paper showed that acute influenza infection of the lung promotes distal melanoma growth in the dermis of the flank and leads to decreased host survival. Here, we proceed to ground the experimental observations in a mechanistic immunobiochemical model that incorporates the T cell receptor signaling pathway, various transcription factors, and a gene regulatory network (GRN). A core component of our model is a biochemical motif, which we call a Triple Incoherent Feed-Forward Loop (TIFFL), and which reflects known interactions between IRF4, Blimp-1, and Bcl-6. The different activity levels of the TIFFL components, as a function of the cognate antigen levels and the given inflammation context, manifest themselves in phenotypically distinct outcomes. Specifically, both the TIFFL reconstruction and quantitative estimates obtained from the model allowed us to formulate a hypothesis that it is the loss of the fundamental TIFFL-induced adaptation of the expression of PD-1 receptors on anti-melanoma CD8+ T cells that constitutes the essence of the previously unrecognized immunologic factor that promotes the experimentally observed distal tumor growth in the presence of acute non-ocogenic infection. We therefore hope that this work can further highlight the importance of adaptive mechanisms by which immune functions contribute to the balance between self and non-self immune tolerance, adaptive resistance, and the strength of TCR-induced activation, thus contributing to the understanding of a broader complexity of fundamental interactions between pathogens and tumors.

  3. A. Rendall and E. D. Sontag. Multiple steady states and the form of response functions to antigen in a model for the initiation of T cell activation. Royal Society Open Science, 4:170821-, 2017. [PDF] Keyword(s): kinetic proofreading, T cells, immunology, systems biology.
    This paper analizes a model for the initial stage of T cell activation. The state variables in the model are the concentrations of phosphorylation states of the T cell receptor complex and the phosphatase SHP-1 in the cell. It is shown that these quantities cannot approach zero, and that there is more than one positive steady state for certain values of the parameters; in addition, damped oscillations are possible. It is also shown that the chemical concentration which represents the degree of activation of the cell, represented by the maximally phosphorylated form of the T cell receptor complex, is in general a non-monotone function of the activating signal. In particular there are cases where there is a value of the dissociation constant of the ligand from the receptor which produces an optimal activation of the T cell. In this way the results of certain simulations in the literature have been confirmed rigorously and new features are discovered.

  4. E.D. Sontag. A dynamical model of immune responses to antigen presentation predicts different regions of tumor or pathogen elimination. Cell Systems, 4:231-241, 2017. [PDF] Keyword(s): scale invariance, fold change detection, T cells, incoherent feedforward loops, immunology, cancer, internal model principle, incoherent feedforward loop, feedforward, IFFL, systems biology.
    Since the early 1990s, many authors have independently suggested that self/nonself recognition by the immune system might be modulated by the rates of change of antigen challenges. This paper introduces an extremely simple and purely conceptual mathematical model that allows dynamic discrimination of immune challenges. The main component of the model is a motif which is ubiquitous in systems biology, the incoherent feedforward loop, which endows the system with the capability to estimate exponential growth exponents, a prediction which is consistent with experimental work showing that exponentially increasing antigen stimulation is a determinant of immune reactivity. Combined with a bistable system and a simple feedback repression mechanism, an interesting phenomenon emerges as a tumor growth rate increases: elimination, tolerance (tumor growth), again elimination, and finally a second zone of tolerance (tumor escape). This prediction from our model is analogous to the ``two-zone tumor tolerance'' phenomenon experimentally validated since the mid 1970s. Moreover, we provide a plausible biological instantiation of our circuit using combinations of regulatory and effector T cells.

  5. E.D. Sontag. Structure and stability of certain chemical networks and applications to the kinetic proofreading model of T-cell receptor signal transduction. IEEE Trans. Automat. Control, 46(7):1028-1047, 2001. [PDF] Keyword(s): zero-deficiency networks, systems biology, biochemical networks, nonlinear stability, dynamical systems, kinetic proofreading, T cells, immunology.
    This paper deals with the theory of structure, stability, robustness, and stabilization for an appealing class of nonlinear systems which arises in the analysis of chemical networks. The results given here extend, but are also heavily based upon, certain previous work by Feinberg, Horn, and Jackson, of which a self-contained and streamlined exposition is included. The theoretical conclusions are illustrated through an application to the kinetic proofreading model proposed by McKeithan for T-cell receptor signal transduction.

Conference articles
  1. E.D. Sontag. Some remarks on a model for immune signal detection and feedback. In Proc. IEEE Conf. Decision and Control, Dec. 2016, pages 2475-2480, 2016. [PDF] Keyword(s): scale invariance, fold change detection, T cells, incoherent feedforward loops, immunology, cancer.
    This is a conference paper related to the journal paper "A dynamical model of immune responses to antigen presentation predicts different regions of tumor or pathogen elimination". The conference paper includes several theorems for a simplified model which were not included in the journal paper.

Internal reports
  1. E.D. Sontag. A remark on incoherent feedforward circuits as change detectors and feedback controllers. Technical report, arXiv:1602.00162, 2016. [PDF] Keyword(s): scale invariance, fold change detection, T cells, incoherent feedforward loops, immunology, incoherent feedforward loop, feedforward, IFFL.
    This note analyzes incoherent feedforward loops in signal processing and control. It studies the response properties of IFFL's to exponentially growing inputs, both for a standard version of the IFFL and for a variation in which the output variable has a positive self-feedback term. It also considers a negative feedback configuration, using such a device as a controller. It uncovers a somewhat surprising phenomenon in which stabilization is only possible in disconnected regions of parameter space, as the controlled system's growth rate is varied.

  2. E.D. Sontag. Two-zone tumor tolerance can arise from a simple immunological feedforward motif that estimates tumor growth rates. Technical report, bioRxiv, 2016. [PDF] Keyword(s): scale invariance, fold change detection, T cells, incoherent feedforward loops, immunology, cancer.
    Preprint version of "A dynamical model of immune responses to antigen presentation predicts different regions of tumor or pathogen elimination", appeared in Cell Systems 2017. However, the journal version does not include Section 9 on degradation-based IFFL's from this preprint.

  3. E.D. Sontag. Incoherent feedforward motifs as immune change detectors. Technical report, bioRxiv, December 2015. [PDF] Keyword(s): scale invariance, fcd, fold change detection, T cells, incoherent feedforward loops, immunology, incoherent feedforward loop, feedforward, IFFL.
    We speculate that incoherent feedforward loops may be phenomenologically involved in self/nonself discrimination in immune-infection and immune-tumor interactions, acting as "change detectors". In turn, this may result in logarithmic sensing (Weber phenomenon) and even scale invariance (fold-change detection).



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Last modified: Wed Aug 17 10:22:08 2022
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