Revising immune cell coordination: Origins and importance of single‐cell variation

Abstract

Moving from the optimalization of single-cell technologies to the interpretation of the multi-complex single-cell data, the field of immunoengineering is granted with numerous important insights into the coordination of immune cell activation and how to modulate it for therapeutic purposes. However, insights come with additional follow-up questions that challenge our perception on how immune responses are generated and fine-tuned to fight a wide array of pathogens in ever-changing and often unpredictable microenvironments. Are immune responses really either being tightly regulated by molecular determinants, or highly flexible attributed to stochasticity? What exactly makes up the basic rules by which single cells cooperate to establish tissue-level immunity? Taking the type I IFN system and its newest insights as a main example throughout this review, we revise the basic concepts of (single) immune cell coordination, redefine the concepts of noise, stochasticity and determinism, and highlight the importance of single-cell variation in immunology and beyond.

Transiently heritable fates and quorum sensing drive early IFN-I response dynamics

“…One possible explanation for the observed higher responsiveness in early generation clones, like described before, lies in the possible effect of cell density dictating responsiveness, which closely relates to the phenomenon called quorum sensing. Intuitively, the immune strategy in which the fraction of responders, in this case IFN-I producers, is based on the amount of available cells seems crucial to establish proper antiviral immunity at any circumstance ( Van Eyndhoven and Tel, 2022 ). Accordingly, a small population of cells needs to contribute to greater extend, involving relatively more responders, than a large population of cells, to ensure the overall IFN-I production is similar.…”

“…However, we do speculate that, in vivo, quorum sensing triggers collective and coordinated actions, as observed in DCs activated in the draining lymph node, in vivo ( Bardou et al, 2021 ). Intuitively, it makes sense that cell density plays a major role in cytokine-mediated responses, while the same antiviral effects are achieved by a high responding fraction of a small population of potential producers, as compared to a low fraction of a large population of potential producers ( Van Eyndhoven and Tel, 2022 ). Although the translation of single-cell work might seem challenging, because of the seemingly unnatural situations mimicked with single-cell work, we believe that the fundamentals of cellular decision-making are similar across numbers, scales, and systems.…”

“…Besides a growing body of evidence on the role of transient heritable fates dictating cellular behaviors, the effects of population density, often referred to as quorum sensing, are getting more established for immune (signaling) systems ( Antonioli et al, 2019 ; Polonsky et al, 2018 ; Van Eyndhoven and Tel, 2022 ). On top of the intrinsic features characterized by stochasticity and determinism, individual immune cells can communicate in various ways to elicit appropriate systemic immune responses.…”

“…Paracrine signaling is defined by cells either secreting signaling molecules without expressing the cognate receptor, or cells expressing the receptor without secreting the molecule. In essence, quorum sensing can be considered a phenomenon in which autocrine cells determine their population density based on cells engaging in neighbor communication, but without self-communication ( Doğaner et al, 2016 ; Van Eyndhoven and Tel, 2022 ). Especially in the presence of other competitive decision makers (i.e., cytokine consumers and producers), it is critical for individual cells to assess cellular density, and act accordingly ( Oyler-Yaniv et al, 2017 ).…”

Immune quorum sensing dictates IFN‐I response dynamics in human plasmacytoid dendritic cells

“…In essence, whether considering single immune cell behaviors or collective population‐wide immune cell behaviors, immune responses are generated by single cells making their own decisions. These decisions (e.g., whether to produce IFN‐Is) are based on the signals they perceive on their cell surface, which must be processed intracellularly, thereby distinguishing noise from actual cues [6]. Additionally, immune cells must anticipate the future state of their environment, thereby weighing the costs and benefits of each possible outcome, in the presence of other potentially competitive decision makers [5].…”