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[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.]
Published: Jan 5, 2021
Keywords: Feedforward loop; Regulation; T cell activation; Sign-sensitive delay; Adaptive immunity; Two-signal theory
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