title: Surgery followed by persistence of high-grade squamous intraepithelial lesions is associated with the induction of a dysfunctional HPV16-specific T-cell response.
abstract: OBJECTIVE
  To characterize HPV16 E6- and E7-specific T-cell immunity in patients with high-grade squamous intraepithelial lesions (HSIL).
  
  
  METHODS
  Peripheral blood mononuclear cells isolated from 38 patients with HPV16+ HSIL were used to determine the magnitude, breadth, and polarization of HPV16-specific T-cell responses by proliferation assays and cytokine assays. Furthermore, HSIL-infiltrating T cells isolated from 7 cases were analyzed for the presence of HPV16 E6- and/or E7-specific T cells, phenotyped, and tested for the specific production of IFN-gamma and interleukin-10 as well as for their capacity to suppress immune responses.
  
  
  RESULTS
  HPV16-specific T-cell responses were absent in the circulation of the majority (approximately 60%) of patients who visit the clinic for treatment of a HPV16+ HSIL lesion. Notably, HPV16-specific T-cell reactivity was predominantly detected in patients returning to the clinic for repetitive treatment of a persistent or recurrent HPV16+ HSIL lesion after initial destructive treatment. The majority (> 70%) of these HPV16-specific T-cell responses did not secrete proinflammatory cytokines, indicating that most of the subjects, although in principle able to mount a HPV16-specific immune response, fail to develop protective cellular immunity. This notion is sustained by our observation that only three HSIL-infiltrating T-cell cultures contained HPV16-specific T cells, one of which clearly consisted of HPV16 E7-specific regulatory T cells.
  
  
  CONCLUSIONS
  The presence of HPV16-specific T cells with a non-Th1/Th2 cytokine and even suppressive signature in patients with HSIL may affect the outcome of vaccine approaches aiming at reinforcing human papillomavirus-specific immunity to attack human papillomavirus-induced lesions.
authors.affiliation: Department of Gynaecology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Peggy J
authors.initials: PJ
authors.lastname: de Vos van Steenwijk
authors.forename: Sytse J
authors.initials: SJ
authors.lastname: Piersma
authors.forename: Marij J P
authors.initials: MJ
authors.lastname: Welters
authors.forename: Jeanette M
authors.initials: JM
authors.lastname: van der Hulst
authors.forename: Gertjan
authors.initials: G
authors.lastname: Fleuren
authors.forename: Bart W J
authors.initials: BW
authors.lastname: Hellebrekers
authors.forename: Gemma G
authors.initials: GG
authors.lastname: Kenter
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
mesh_terms: D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000601:surgery; D049109:Cell Proliferation; D005260:Female; D052162:Human papillomavirus 16 / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000821:virology; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000276:immunology* / Q000601:surgery; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000601:surgery / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000276:immunology* / Q000601:surgery / Q000821:virology
chemical_list: D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D016753:Interleukin-10; D007371:Interferon-gamma