Successive annual influenza vaccination induces a recurrent oligoclonotypic memory response in circulating T follicular helper cells
Open accessAbstract
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. Here, we identified a cTfh population that expressed multiple T cell activation markers and could be readily identified by coexpression of ICOS and CD38. This subset expressed more Bcl-6, c-Maf, and IL-21 than 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 (AIM) expression. Moreover, TCRB sequencing identified a clonal response in ICOS+CD38+ cTfh that correlated strongly with the increased circulating ICOS+CD38+ cTfh frequency and the circulating plasmablast response. In subjects 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 ICOS-CD38- cTfh repertoire in subsequent years, suggesting clonal maintenance in a memory reservoir in the more-stable ICOS-CD38- 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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The AIM assay accurately detects cTfh that are known to contain antigen-specific T cells in other contexts.
“indicating that the AIM assay accurately captures cTfh known to contain antigen-specific T cells in other settings (Herati et al., 2017).”
From Rapid induction of antigen-specific CD4+ T cells is associated with coordinated humoral and cellular immunity to SARS-CoV-2 mRNA vaccination (2021) · cites this paper as Herati et al., 2017
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- Authors
- Herati, R. S., Muselman, A., Vella, L., Bengsch, B., Parkhouse, K., Del Alcazar, D., Kotzin, J., Doyle, S. A., Tebas, P., Hensley, S. E., Su, L. F., Schmader, K. E., & Wherry, E. J.
- Affiliations
- University of Pennsylvania (US)
- Children's Hospital of Philadelphia (US)
- The Wistar Institute (US)
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
- Duke Medical Center (US)
- Corresponding author
- Herati, Ramin Sedaghat
- Wherry, E. John
- ORCID
- Venue
- Science Immunology
- Published
- 2017-02-24
- Volume
- 2
- Issue
- 8
- ISSN
- 2470-9468 (ISSN-L)
- PMC
- PMC5469419
- OpenAlex
- W2588137025
- Cited by
- 167
- References
- 49
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 16 · 2023: 17 · 2022: 22 · 2021: 34 · 2020: 19 · 2019: 23 · 2018: 10 · 2017: 9
- FWCI
- 7.66
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Science Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (award295646, AG047773, AG028716)
- National Institute of Allergy and Infectious Diseases (award295647, AI114852, AI045008, AI113047, AI108686, AI112521, AI117950, AI2010085)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- T follicular helper cells, influenza vaccination, annual vaccination, ICOS, CD38, B cell help, plasmablasts, BCL6, c-Maf, IL-21, T cell memory
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