Figure 4: A model for the generation of high-avidity Abs in TIV vaccination.

(a) Healthy individuals have a broad range of pre-existing antigen-experienced B cells that recognize a specific HA1 epitope at different affinities. When vaccination successfully induces a preferential expansion of high affinity clones and their differentiation into Ab-producing cells, vaccination induces an increase in the avidity of Abs. (b) High affinity B cells have an advantage over low affinity cells to capture and present antigens to ICOS⁺PD-1⁺CXCR3⁺ Tfh cells for cognate interactions. These interactions occur at extrafollicular sites, and induce high affinity clones to undergo extensive proliferation and differentiation into Ab-producing cells. ICOS⁺PD-1⁺CXCR3⁺ Tfh cells are composed of heterogeneous populations that recognize wide range of influenza proteins, which contributes to increase the chance to engage cognate interactions with any high affinity clones. Such selective activation and expansion of high affinity B cells contribute to the rapid increase of Ab avidity.