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Dynamic Regulation of T Cell Activation by Coupled Feedforward Loops

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Infectious Diseases and Our Planet

Part of the book series: Mathematics of Planet Earth ((MPE,volume 7))

Abstract

The adaptive immune system responds to threats by activating T cells. However, this response is perilous if T cells are activated by the wrong signal or longer than necessary. It is therefore important that T cells get activated only by the right kind of signals and for the right duration. The dominant theory in immunology during recent decades has been that a T cell must receive at least two signals before it can become activated. It is, however, unclear whether and how this two-signal requirement ensures that T cell activation is provoked only by the right signals and that the response is just long enough. Here, we propose a novel, empirically founded hypothesis—i.e. the two-signal requirement induces a coherent feedforward loop motif, which prevents T cells from responding to spurious antigen signals, and ensures the response is quickly switched off once a persistent antigen signal has been cleared. Further consideration of the interaction between effector and regulatory T cells produces a coupled coherent-incoherent feedforward loop, analysis of which predicts that, in order for the effector cells to orchestrate immune responses before they are suppressed by the regulatory cells, the latter cells must have a higher costimulation threshold than the former. Strikingly, this prediction is supported by experimental data. Together, our results provide a novel perspective on the dynamical implications of the two-signal requirement for T cell activation.

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Author information

Authors and Affiliations

  1. African Institute for Mathematical Sciences, Cape Town, South Africa

    Gershom Buri

  2. SACEMA, Stellenbosch University, Cape Town, South Africa

    Gershom Buri

  3. African Institute for Mathematical Sciences, Limbe, Cameroon

    Girma Mesfin Zelleke

  4. Research Department, African Institute for Mathematical Sciences Global Secretariat, Kigali, Rwanda

    Wilfred Ndifon

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  1. Gershom Buri
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  2. Girma Mesfin Zelleke
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  3. Wilfred Ndifon
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Correspondence to Wilfred Ndifon .

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Editors and Affiliations

  1. Department of Mathematics, Lehigh University, Bethlehem, PA, USA

    Miranda I. Teboh-Ewungkem

  2. Department of Mathematics, University of Buea, Buea, Cameroon

    Gideon Akumah Ngwa

1 Electronic Supplementary Material

Fig. S1

Dynamics of C1-FFL with an AND gate input function and an exponentially increasing antigen signal. Activation of T effector cells waits until the costimulation signal passes the activation threshold. As expected, based on Eqs. (1) and (5), the waiting time decreases as the growth rate of the antigen signal increases due to a corresponding increase in the costimulation signal. In addition, the point at which the Te response converges increases with the growth rate up to a maximum. Parameter values used were: βc = βTe = αc = αe = KAC = KATe = KCTe = μ = 1, n = 4. λ was set to 0.1 (a), 0.5 (b) and 0.9 (c) (PNG 55 kb)

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Buri, G., Zelleke, G.M., Ndifon, W. (2021). Dynamic Regulation of T Cell Activation by Coupled Feedforward Loops. In: Teboh-Ewungkem, M.I., Ngwa, G.A. (eds) Infectious Diseases and Our Planet. Mathematics of Planet Earth, vol 7. Springer, Cham. https://doi.org/10.1007/978-3-030-50826-5_9

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