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.