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.

Figure 1:. Bottom-up cell fate control in the immune system.

Embryos (left) and other systems rely on pre-defined spatial cues and constraints to determine the sizes and fractions of differentiated cell populations. In contrast, the immune system (right) uses autonomous bottom-up mechanisms to regulate cell fate decisions in dividing precursors for population control.

Figure 2:. Rare, stochastic events controlling cell fate decisions.

(A) Regulatory systems consisting of many component molecules (left) or fast reaction rates relative to cellular response timescales (middle) generate deterministic, homogenous responses at the single-cell level. In contrast, regulatory systems consisting of slow events involving low copy-numbers of component molecules (right) generate stochastic, heterogeneous responses at the single-cell level. Both deterministic and stochastic regulatory mechanisms allow for predictable population-level responses. The rate of the regulatory event, represented as the transition from gray to green circles, and the concentration of component molecules dictate the response dynamics (generation of blue squares) as shown for two hypothetical cells. Only stochastic regulation can give rise to a bimodal population in response to homogenous signals. (B) Energetically unfavorable nucleation (signal transduction) or dissolution (epigenetic regulation) of condensates involving multivalent interactions between regulatory factors can give rise to rare, stochastic events over long time scales.

Figure 3:. Functions of stochasticity.

(A) The independence of stochastically regulated gene programs enables generation of mixed functional states in response to mixed signals, in contrast to deterministically regulated binary states. These mixed states may range from cells co-expressing independently regulated receptors or cytokines to epigenetically and transcriptomically hybrid cells expressing multiple fate-specifying transcription factors. (B) The heritable nature of epigenetic regulation allows precursor cells to expand in cell number prior to differentiation when the activation rate of a fate-commitment gene is slower than that of cell division.