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

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.