Frequent display of human papillomavirus type 16 E6-specific memory t-Helper cells in the healthy population as witness of previous viral encounter

Marij J P Welters, Annemieke de Jong, Susan J F van den Eeden, Jeanette M van der Hulst, Kitty M C Kwappenberg, Sabrin Hassane, Kees L M C Franken, Jan Wouter Drijfhout, Gert Jan Fleuren, Gemma Kenter, Cornelis J M Melief, Rienk Offringa, Sjoerd H van der Burg

Research output: Contribution to journalArticleAcademicpeer-review


Genital human papillomavirus (HPV) infection is common and the majority of infected individuals successfully deal with this virus. Clearance of HPV is presumably mediated by T cells but HPV-16-specific T-cell memory was usually detected in patients with progressive disease and not in healthy subjects, suggesting that HPV-immunity comes too late. We now show the presence of HPV-16 E6-specific memory T-helper (Th) responses in a major fraction (12 of 20) of healthy individuals by application of the IFN-gamma-ELISPOT assay. Although nearly all E6-peptides were recognized, the majority of the responders targeted peptide sequences of the COOH-terminal half (E6(81-158)) of HPV-16 E6. In a direct comparison, the presence of HPV-16 E6-specific T cells coincided with HPV-16 E2-specific T-cell reactivity in healthy individuals, whereas hardly any HPV-16 E7-specific Th immunity was found. This indicates that the induction of T-cell reactivity against HPV-16 E7 is suboptimal during infection when compared with that against HPV-16 E2 and HPV-16 E6. In conclusion, the presence of HPV-16 E6-specific Th memory in the healthy population demonstrates that HPV infection leads to T-cell immunity against immediate early proteins expressed during infection. Because this HPV-16 E6-specific T-cell immunity was frequently detected in healthy subjects, our data suggest that the observed IFN-gamma-producing proliferating T cells circulating in the peripheral blood play a role in protection against persistent HPV infection and associated development of malignancies.

Original languageEnglish
Pages (from-to)636-641
JournalCancer Research
Issue number3
Publication statusPublished - 1 Feb 2003
Externally publishedYes


  • Adult
  • Aged
  • Epitopes, T-Lymphocyte/immunology
  • Female
  • Humans
  • Immunologic Memory/immunology
  • Interferon-gamma/immunology
  • Lymphocyte Activation/immunology
  • Male
  • Middle Aged
  • Oncogene Proteins, Viral/immunology
  • Papillomaviridae/immunology
  • Papillomavirus E7 Proteins
  • Papillomavirus Infections/immunology
  • Repressor Proteins
  • T-Lymphocytes, Helper-Inducer/immunology
  • Tumor Virus Infections/immunology
  • Uterine Cervical Neoplasms/immunology


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