Successive annual influenza vaccination induces a recurrent oligoclonotypic memory response in circulating T follicular helper cells.

T follicular helper (T_FH) CD4 cells are crucial providers of B cell help during adaptive immune responses. A circulating population of CD4 T cells, termed cT_FH, have similarity to lymphoid T_FH, can provide B cell help, and responded to influenza vaccination. However, it is unclear whether human vaccination-induced cT_FH respond in an antigen-specific manner and whether they form long-lasting memory. We identified a cT_FH population that expressed multiple T cell activation markers and could be readily identified by coexpression of inducible costimulator (ICOS) and CD38. This subset expressed more Bcl6, c-Maf, and interleukin-21 than did other blood CD4 subsets. Influenza vaccination induced a strong response in the ICOS⁺CD38⁺ cT_FH at day 7, and this population included hemagglutinin-specific cells by tetramer staining and antigen-stimulated activation-induced marker expression. Moreover, T cell receptor β chain sequencing identified a clonal response in ICOS⁺CD38⁺ cT_FH that strongly correlated with the increased cT_FH frequency and was associated with the circulating plasmablast response. In participants who received successive annual vaccinations, a recurrent oligoclonal response was identified in the ICOS⁺CD38⁺ cT_FH subset at 7 days after every vaccination. These oligoclonal responses in ICOS⁺CD38⁺ cT_FH after vaccination persisted in the ICOS⁻CD38⁻ cT_FH repertoire in subsequent years, suggesting clonal maintenance in a memory reservoir in the more stable ICOS⁻CD38⁻ cT_FH subset. These data highlight the antigen specificity, lineage relationships, and memory properties of human cT_FH responses to vaccination, providing new avenues for tracking and monitoring cT_FH responses during infection and vaccination in humans. [ABSTRACT FROM AUTHOR]