Balancing speed and accuracy of polyclonal T cell activation: a role for extracellular feedback

Yonatan Savir,Nir Waysbort,Nir Friedman,Yaron E Antebi,Tsvi Tlusty

doi:10.1186/1752-0509-6-111

Abstract

BackgroundExtracellular feedback is an abundant module of intercellular communication networks, yet a detailed understanding of its role is still lacking. Here, we study interactions between polyclonal activated T cells that are mediated by IL-2 extracellular feedback as a model system.ResultsUsing mathematical modeling we show that extracellular feedback can give rise to opposite outcomes: competition or cooperation between interacting T cells, depending on their relative levels of activation. Furthermore, the outcome of the interaction also depends on the relative timing of activation of the cells. A critical time window exists after which a cell that has been more strongly activated nevertheless cannot exclude an inferior competitor.ConclusionsIn a number of experimental studies of polyclonal T-cell systems, outcomes ranging from cooperation to competition as well as time dependent competition were observed. Our model suggests that extracellular feedback can contribute to these observed behaviors as it translates quantitative differences in T cells’ activation strength and in their relative activation time into qualitatively different outcomes. We propose extracellular feedback as a general mechanism that can balance speed and accuracy – choosing the most suitable responders out of a polyclonal population under the clock of an escalating threat.

Highlights

Extracellular feedback is an abundant module of intercellular communication networks, yet a detailed understanding of its role is still lacking
Recent work [16,17] described IL-2 mediated suppression of effector T cells (Teff ) by T regulatory cells (Treg), showing the conditions under which competition for IL-2 serves as an efficient suppression mechanism
T cell interactions mediated by IL-2 extracellular feedback can result in opposite outcomes: competition or cooperation We show that intercellular interactions mediated by IL-2 and amplified by the extracellular positive feedback on IL-2R levels can account for both competition and cooperation between activated T cells

Summary

Introduction

Extracellular feedback is an abundant module of intercellular communication networks, yet a detailed understanding of its role is still lacking. In multicellular systems, positive feedback can be mediated by a secreted molecule which acts either in an autocrine fashion (on the secreting cell) or paracrinally (on nearby cells) [9] This leads to a collective cellular response, during which cells communicate their state to nearby cells using the extracellular signaling molecule. Extracellular feedback driven by IL-2 can affect polyclonal interactions between effector T cells of different antigen specificities, which interact during their priming within lymphoid organs. These interactions between T cells, together with other factors such as availability of co-stimulatory signals, can shape the repertoire of responding T cells through inter-clonal cooperation and competition [18]

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