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.

Keywords: cellular decision-making; heterogeneity; interferons; stochasticity.

Figure 1

Encoding and decoding of immune cell dynamics. In the process of cellular decision‐making, inputs (e.g., viral loads) are encoded by the individual cells. This information is transmitted via intracellular signaling pathways into functional outcomes (e.g., cytokine production), which is referred to as decoding. Figure created using BioRender (https://biorender.com/)

Figure 2

Cellular decision‐making influenced by noise, stochasticity, and determinism. Noise is defined by fluctuations in inputs that do not initiate any different cellular outcome. In contrast, stochastic inputs lead to various cellular responses, despite the input can be exactly similar across cells. Determinism is characterized by similar cellular responses based on various inputs. Figure created using BioRender (https://biorender.com/)

Figure 3

Revising modes of immune cell communication. Cytokine‐mediated immune cell communication can occur in various ways. Autocrine signaling is characterized by self‐communication, in which the signaling molecules activate cognate receptors expressed by the producing cell itself. On the other side of the spectrum is paracrine signaling, which is characterized by neighbor communication. This implies that signaling molecules diffuse to neighboring cells expressing the cognate receptors. Quorum sensing involves both autocrine and paracrine signaling, during which responsiveness is dictated by signal molecule density. Figure created using BioRender (https://biorender.com/)

Figure 4

Hypotheses explaining the functional importance of single‐cell differences. According to the response distribution hypothesis (1), cellular heterogeneity dictates binary cellular decision‐making, while only a fraction of cells is able to elicit responses given its intrinsic (molecular) status. The fate plasticity and priming hypothesis (2) describes fluctuations in regulators of cell fates, allowing subpopulations of cells to be primed to respond (ON). Therefore, cell switch fate throughout (from ON to OFF, and vice versa), determined by kinetic parameters (k_on and k_off), which can be influenced by priming. Finally, the crowd control hypothesis (3) entails the presence of a rare subpopulation with a predetermined fate to become a responding cell upon response initiation. Figure created using BioRender (https://biorender.com/)