Quorum sensing via dynamic cytokine signaling comprehensively explains divergent patterns of effector choice among helper T cells

In the animal kingdom, various forms of swarming enable groups of autonomous individuals to transform uncertain information into unified decisions which are probabilistically beneficial. Crossing scales from individual to group decisions requires dynamically accumulating signals among individuals. In striking parallel, the mammalian immune system is also a group of decentralized autonomous units (i.e. cells) which collectively navigate uncertainty with the help of dynamically accumulating signals (i.e. cytokines). Therefore, we apply techniques of understanding swarm behavior to a decision-making problem in the mammalian immune system, namely effector choice among CD4+ T helper (Th) cells. We find that incorporating dynamic cytokine signaling into a simple model of Th differentiation comprehensively explains divergent observations of this process. The plasticity and heterogeneity of individual Th cells, the tunable mixtures of effector types that can be generated in vitro, and the polarized yet updateable group effector commitment often observed in vivo are all explained by the same set of underlying molecular rules. These rules reveal that Th cells harness dynamic cytokine signaling to implement a system of quorum sensing. Quorum sensing, in turn, may confer adaptive advantages on the mammalian immune system, especially during coinfection and during coevolution with manipulative parasites. This highlights a new way of understanding the mammalian immune system as a cellular swarm, and it underscores the power of collectives throughout nature.Author summary: Across the animal kingdom, swarming is a common phenomenon by which many autonomous individuals act as a unified group. Similarly, helper T cells in the mammalian immune system are numerous and autonomous, and yet they collectively make important decisions, such as which immune weapons to recruit during a given infection (i.e. “effector choice”). However, due to varying experimental results, it is unclear when, how, and why helper T cells coordinate unified effector choices. Inspired by studies of swarms in the animal kingdom, we answer all three questions with a single set of simple mathematical rules governing the interactions of individual cells. Helper T cells engage in quorum sensing, transitioning from mixed to unified group decisions only at high cell densities. Quorum sensing emerges naturally from the interplay between molecular circuits within helper T cells and dynamically accumulating signals between helper T cells. Quorum sensing may have evolved because it helps our immune systems discern legitimate changes in effector needs from parasitic sabotage of the effector choice system. These insights demonstrate that the quantitative study of swarm biology can shed new light on the organization and function of the mammalian immune system.