Influenza vaccination stimulates maturation of the human T follicular helper cell response

The differentiation and specificity of human CD4⁺ T follicular helper cells (T_FH cells) after influenza vaccination have been poorly defined. Here we profiled blood and draining lymph node (LN) samples from human volunteers for over 2 years after two influenza vaccines were administered 1 year apart to define the evolution of the CD4⁺ T_FH cell response. The first vaccination induced an increase in the frequency of circulating T_FH (cT_FH) and LN T_FH cells at week 1 postvaccination. This increase was transient for cT_FH cells, whereas the LN T_FH cells further expanded during week 2 and remained elevated in frequency for at least 3 months. We observed several distinct subsets of T_FH cells in the LN, including pre-T_FH cells, memory T_FH cells, germinal center (GC) T_FH cells and interleukin-10⁺ T_FH cell subsets beginning at baseline and at all time points postvaccination. The shift toward a GC T_FH cell phenotype occurred with faster kinetics after the second vaccine compared to the first vaccine. We identified several influenza-specific T_FH cell clonal lineages, including multiple responses targeting internal influenza virus proteins, and found that each T_FH cell state was attainable within a clonal lineage. Thus, human T_FH cells form a durable and dynamic multitissue network.