Regulatory T cells set a dynamic boundary between cellular and humoral immunity based on input signal kinetics 2258109

Abstract Introduction The adaptive immune system defends through two strategies: humoral immunity, mediated by antibodies that require long timescales to achieve high affinity and durable protection, and cellular immunity, mediated by effector T cells that act rapidly to eliminate infected or damaged cells. Because these responses rely on overlapping resources, the immune system faces a fundamental trade-off between establishing humoral or cellular responses. We propose that regulatory T cells (Tregs) dynamically set this balance. Tregs control the availability of interleukin-2 (IL-2), biasing activated T cells toward either T follicular helper (Tfh) fates–which promote germinal center formation–or non-Tfh effectors, favoring cellular immunity. Since Treg consumption of IL-2 scales with T cell activation, cellular immunity is prioritized when threats escalate rapidly and humoral immunity when they progress more gradually. Methods We modeled IL-2 availability and T cell differentiation during immune responses of differing kinetics in silico using a continuous-time Markov chain framework. Predictions were then tested in vivo by varying challenge kinetics and applying high-resolution multiplexed imaging to quantify activated T cell fates, Treg dynamics, and germinal center formation over time. Results The model predicted that 1) expanding challenges favored non-Tfh effector differentiation, whereas transient or prolonged challenges favored Tfh differentiation and germinal center formation, and 2) Tregs controlled this partitioning by scaling IL-2 consumption with total challenge burden. These predictions were validated in vivo by comparing immunization strategies. Conclusion Our findings provide evidence that Tregs dynamically tune Tfh versus non-Tfh effector differentiation according to the kinetics of the immune challenge. This framework introduces a new paradigm for how Tregs govern trade-offs between cellular and humoral immunity, with broad implications for vaccination, cancer, and autoimmunity. Funding Source This material is based upon work supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number T32GM087237, by the Ragon Institute under a Strategic Initiative grant, by Massachusetts General Hospital, and by the Massachusetts Institute of Technology. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)