Fig. 1: Roles of Tfh cells in humoral response after influenza vaccination.

Healthy subjects display a broad range of pre-existing memory B cells recognizing influenza antigens with different affinities (indicated by different colors). Influenza-specific Tfh1 cells become activated and expanded within 7 days post-vaccination. Current evidence suggests that cTfh1 cells are mainly involved in the selection of high-affinity B cells and their differentiation towards plasmablasts. High-affinity B cells likely have an advantage over low-affinity cells to retrieve and present antigens to Tfh1 cells, and a prolonged interaction between high-affinity memory B cells and Tfh1 cells might promote B cell differentiation towards plasmablasts. These interactions likely occur at the T:B border, but not within GCs, and both the activated Tfh1 cells and plasmablasts exit the lymph nodes at day 7 post-vaccination. By contrast, where and how influenza vaccination induces the expansion and/or generation of influenza-specific CD27⁺CD21^lo B cells and CD27⁺CD21^hi classical memory cells, and how Tfh cells contribute to their generation remain unclear. Regarding the contribution of Tfh cells, two models can be considered. In model 1, memory B cells with lower affinities may briefly interact with the activated Tfh1 cells before Tfh1 cells exit from the lymph nodes. This short interaction might be sufficient for expansion of CD27⁺CD21^hi classical memory B cells and differentiation towards CD27⁺CD21^lo B cells. In models 2, memory B cells with lower affinities may primarily interact with a Tfh subset that remains in the lymph nodes for an extended period (indicated as Tfhx). Tfhx cells might be a part of the activated Tfh1 cells or different Tfh subsets. The Tfhx cells might be involved in the formation of GCs and contribute to the generation of CD27⁺CD21^lo B cells. In either model, the current evidence suggests that the diversification of memory B cell repertoire through this mechanism by the current influenza vaccine is suboptimal. While this illustration shows the development of GCs at day > 14 days, the magnitude of GC response seems low. PB: plasmablast.