Dynamic role of T follicular helper cells in shaping B cell affinity maturation*

In the humoral immune response, B cells that produce high-affinity antibodies are generated through a Darwinian evolutionary process called affinity maturation. Affinity maturation, which takes place in germinal centers (GC), is driven by cycles of (1) selection mediated by T follicular helper (TFH) cells, (2) division, and (3) hypermutation of B cells. Recently, it was found that TFH cells themselves also exhibit dynamic behavior throughout the course of the GC reaction, undergoing affinity-dependent proliferation. Specifically, those TFH cells expressing T cell receptors (TCRs) with higher affinity to the peptide presented by B cells undergo more rapid proliferation. How does this dynamic behavior of TFH cells influence B cell affinity maturation? To address this question, we developed a population dynamics model which explicitly incorporates TFH cell properties and proliferation. Notably, TFH cell-mediated selection of B cells is found to be the rate limiting step, so sufficient proliferation of TFH cells is required to alleviate a potential bottleneck. Moreover, we find that increasing TCR affinity over time is necessary for efficient affinity maturation, where this crucial enhancement can be achieved through affinity-dependent proliferation and inter-GC migration of TFH cells.