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 beta 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.