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

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Science Immunology  17 Feb 2017:
Vol. 2, Issue 8, eaag2152
DOI: 10.1126/sciimmunol.aag2152

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Remembering TFH cell help

Immunological memory operates on the assumption that if you’re exposed to an infection once, you’re more likely to be exposed again. Chance favors the prepared, and the memory response is bigger, faster, and stronger. Now, Herati et al. examine immunological memory in humans who have received successive annual influenza vaccinations. They find that circulating T follicular helper cells, which provide B cell help, not only respond to influenza vaccination but also form long-lasting memory. These cells may serve as markers for successful vaccination as well as targets for new vaccines.


T follicular helper (TFH) CD4 cells are crucial providers of B cell help during adaptive immune responses. A circulating population of CD4 T cells, termed cTFH, have similarity to lymphoid TFH, can provide B cell help, and responded to influenza vaccination. However, it is unclear whether human vaccination-induced cTFH respond in an antigen-specific manner and whether they form long-lasting memory. We identified a cTFH 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+ cTFH 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+ cTFH that strongly correlated with the increased cTFH 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+ cTFH subset at 7 days after every vaccination. These oligoclonal responses in ICOS+CD38+ cTFH after vaccination persisted in the ICOSCD38 cTFH repertoire in subsequent years, suggesting clonal maintenance in a memory reservoir in the more stable ICOSCD38 cTFH subset. These data highlight the antigen specificity, lineage relationships, and memory properties of human cTFH responses to vaccination, providing new avenues for tracking and monitoring cTFH responses during infection and vaccination in humans.

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