Cytokines control the physical state of immune tissue

Unlike most solid-like tissues, immune tissue is protean and reconfigurable--its component cells can patrol vast territories, find rare cellular partners, and dynamically self-organize into functional structures like germinal centers or tertiary lymphoid structures. The ability of immune cells to collectively behave as an active material that switches physical state is essential for adaptive immunity. Yet the principles governing the control of the physical properties of immune tissues, and how chemical and mechanical forms of control interplay remain obscure. Inspired by minimal immune cell components that recapitulate germinal center (GC) dynamics, we developed an agent-based model that predicted that a tissues ability to program its own physical properties governs the efficiency of antibody evolution. This motivated our search for biomolecular forms of control capable of tuning this material property. Using a tractable in vitro model, we found that CD40L-stimulated human B cells self-organize into active, liquid-like condensates that round, fuse, and internally mix. GC cytokines IL-4 and IL-21 tuned this effective temperature, driving phase transitions from cohesive, liquid-like states to dispersed, gas-like morphologies. These findings demonstrate that cytokines control tissue fluidity, suggesting a previously unrecognized biophysical form of immune regulation. Significance StatementThe bodys immune system is uniquely flexible, allowing cells to organize into temporary structures, like germinal centers or tertiary lymphoid structures, to fight intruders. How this physical flexibility is controlled is a major question. We discovered that the physical state of immune tissue is chemically programmable. We show that self-organized multicellular B cell structures behave like liquid droplets, and we used this framework to demonstrate that signals (cytokines) can modulate their physical properties. This finding identifies a new biophysical axis of immune control, suggesting the body actively tunes its tissue fluidity to optimize the immune response.