Modeling the Synergetic Dynamics of B cells and TFH cells in Germinal Center Reactions.

B cells producing high-affinity antibodies arise through affinity maturation within germinal centers (GCs), where selection is driven by T follicular helper (TFH) cells. Recent studies have shown that, like GC B cells, TFH cells also undergo antigen-dependent selection, with competition among TFH clones dictated by their ability to recognize and stimulate B cells. This sensitivity-dependent selection process leads to dynamic remodeling of the TFH repertoire over time. Despite the essential role of TFH cells in B cell selection, the functional consequences of the time evolution of the TFH cell population remains poorly understood. To address this gap, we developed a population dynamics model that explicitly incorporates key TFH cell properties and dynamics. Our analysis predicts that dynamic feedback between B and TFH cell populations provides robust homeostatic regulation of their numbers in the GC, yielding a stable lymphocyte ratio that we verify experimentally. Moreover, our model predicts that TFH clone sensitivity dictates distinct evolutionary strategies during affinity maturation, with low-sensitivity TFH cells accelerating affinity gain at the expense of B cell diversity, while high-sensitivity TFH cells slow affinity maturation but preserve a broader B cell repertoire. These findings highlight the importance of co-regulation between TFH and B cells and suggest that reciprocal stimulation allows the immune system to tune the tradeoff between the speed of affinity gain and the breadth of B cell diversity-a principle that may extend to other adaptive systems.