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

Using 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.In 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.Positive feedback is common in biological and ecological systems [1,2], and has been shown to generate various behaviors including bistability [3] and hysteresis [4]. Intracellular positive feedback, which serves as a common module of gene regulatory networks, has been extensively studied both theoretically and experimentally [5-8]. However, 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. Although extracellular positive feedback serves as a basic building block of intercellular communication networks (Figure 1A), a detailed understanding of its function is still missing.The immune system offers numerous examples of extracellular positive