Order by chance: origins and benefits of stochasticity in immune cell fate control

Abstract To protect against diverse challenges, the immune system must continuously generate an arsenal of specialized cell types, each of which can mount a myriad of effector responses upon detection of potential threats. To do so, it must generate multiple differentiated cell populations with defined sizes and proportions, often from rare starting precursor cells. Here, we discuss the emerging view that inherently probabilistic mechanisms, involving rare, rate-limiting regulatory events in single cells, control fate decisions and population sizes and fractions during immune development and function. We first review growing evidence that key fate control points are gated by stochastic signaling and gene regulatory events that occur infrequently over decision-making timescales, such that initially homogeneous cells can adopt variable outcomes in response to uniform signals. We next discuss how such stochastic control can provide functional capabilities that are harder to achieve with deterministic control strategies, and may be central to robust immune system function.