Graduate Student Massachusetts Institute of Technology, United States
Disclosure(s):
Amy Huang: No financial relationships to disclose
Introduction/Rationale: 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.
