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Simulation of stimulation: Cytokine dosage and cell cycle crosstalk driving timing-dependent T cell differentiation

Barberis, Matteo, Helikar, T. and Verbruggen, P. (2018) Simulation of stimulation: Cytokine dosage and cell cycle crosstalk driving timing-dependent T cell differentiation Frontiers in Physiology, 9. pp. 879-896.

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Triggering an appropriate protective response against invading agents is crucial to the effectiveness of human innate and adaptive immunity. Pathogen recognition and elimination requires integration of a myriad of signals from many different immune cells. For example, T cell functioning is not qualitatively, but quantitatively determined by cellular and humoral signals. Tipping the balance of signals, such that one of these is favored or gains advantage on another one, may impact the plasticity of T cells. This may lead to switching their phenotypes and, ultimately, modulating the balance between proliferating and memory T cells to sustain an appropriate immune response. We hypothesize that, similar to other intracellular processes such as the cell cycle, the process of T cell differentiation is the result of: (i) pleiotropy (pattern) and (ii) magnitude (dosage/concentration) of input signals, as well as (iii) their timing and duration. That is, a flexible, yet robust immune response upon recognition of the pathogen may result from the integration of signals at the right dosage and timing. To investigate and understand how system's properties such as T cell plasticity and T cell-mediated robust response arise from the interplay between these signals, the use of experimental toolboxes that modulate immune proteins may be explored. Currently available methodologies to engineer T cells and a recently devised strategy to measure protein dosage may be employed to precisely determine, for example, the expression of transcription factors responsible for T cell differentiation into various subtypes. Thus, the immune response may be systematically investigated quantitatively. Here, we provide a perspective of how pattern, dosage and timing of specific signals, called interleukins, may influence T cell activation and differentiation during the course of the immune response. We further propose that interleukins alone cannot explain the phenotype variability observed in T cells. Specifically, we provide evidence that the dosage of intercellular components of both the immune system and the cell cycle regulating cell proliferation may contribute to T cell activation, differentiation, as well as T cell memory formation and maintenance. Altogether, we envision that a qualitative (pattern) and quantitative (dosage) crosstalk between the extracellular milieu and intracellular proteins leads to T cell plasticity and robustness. The understanding of this complex interplay is crucial to predict and prevent scenarios where tipping the balance of signals may be compromised, such as in autoimmunity.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
Helikar, T.
Verbruggen, P.
Date : 2 August 2018
DOI : 10.3389/fphys.2018.00879
Copyright Disclaimer : © 2018 Barberis, Helikar and Verbruggen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Uncontrolled Keywords : (memory) T cell differentiation; Autoimmunity; CDK; Cell cycle; Cytokine activation timing; Cytokine dosage; MAmTOW; P27Kip1
Depositing User : Clive Harris
Date Deposited : 12 Apr 2019 11:38
Last Modified : 03 Oct 2019 11:05

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