biostudies-literatureSchattgen SANIAID NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious DiseasesU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)1742-1753https://www.ebi.ac.uk/biostudies/studies/S-EPMC11362011biostudies-literatureUnknown25(9)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.Nature immunologyInfluenza vaccination stimulates maturation of the human T follicular helper cell response.PMC11362011F32 AI157296R21 AI13981375N93021C00016U01 AI144616R01 AI136514F32AI157296R01AI136514U01 AI141990U01AI144616U01 AI15074775N93019C00052HHSN272201400006CSchmitz AJMettelman RCTurner JSKlebert MKKim HEllebedy AHGhonim MAZhou JQSchattgen SAHaile ASuessen TMiddleton WDKim WAwad WMcIntire KMPresti RMCrawford JCTeefey SAThomas PGfalseInfluenza 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.2024-01-01T00:00:00Z2024 Sep2026-05-04T06:47:22.312Z2025-04-06T13:45:04.627ZS-EPMC113620113916447710.1038/s41590-024-01926-6