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T-cell responses to human papillomavirus type 16 among women with different grades of cervical neoplasia.

Steele JC, Mann CH, Rookes S, Rollason T, Murphy D, Freeth MG, Gallimore PH, Roberts S - Br. J. Cancer (2005)

Bottom Line: T-cell responses were observed in the majority (78%) of samples.CD8+ reactivity to E6 peptides was dominant across all disease grades, inferring that E6-specific CD8+ T cells are not vitally involved in disease clearance.Our study reveals significant differences in HPV16 immunity during progressive CIN.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. j.c.steele@bham.ac.uk

ABSTRACT
Infection with high-risk genital human papillomavirus (HPV) types is a major risk factor for the development of cervical intraepithelial neoplasia (CIN) and invasive cervical carcinoma. The design of effective immunotherapies requires a greater understanding of how HPV-specific T-cell responses are involved in disease clearance and/or progression. Here, we have investigated T-cell responses to five HPV16 proteins (E6, E7, E4, L1 and L2) in women with CIN or cervical carcinoma directly ex vivo. T-cell responses were observed in the majority (78%) of samples. The frequency of CD4+ responders was far lower among those with progressive disease, indicating that the CD4+ T-cell response might be important in HPV clearance. CD8+ reactivity to E6 peptides was dominant across all disease grades, inferring that E6-specific CD8+ T cells are not vitally involved in disease clearance. T-cell responses were demonstrated in the majority (80%) of cervical cancer patients, but are obviously ineffective. Our study reveals significant differences in HPV16 immunity during progressive CIN. We conclude that the HPV-specific CD4+ T-cell response should be an important consideration in immunotherapy design, which should aim to target preinvasive disease.

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Summary of the ELISPOT assay data. The percentages of positive ELISPOT responses obtained generally (A), in relation to disease grade (B), CD4 and CD8 responses in relation to disease grade (C), and the antigen specificities of the CD4+ and CD8+ T-cell reactivities in relation to disease grade (D). ▒ represents no CIN, □ low-grade disease, ▓ high-grade disease, and ▪ cervical cancer.
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fig2: Summary of the ELISPOT assay data. The percentages of positive ELISPOT responses obtained generally (A), in relation to disease grade (B), CD4 and CD8 responses in relation to disease grade (C), and the antigen specificities of the CD4+ and CD8+ T-cell reactivities in relation to disease grade (D). ▒ represents no CIN, □ low-grade disease, ▓ high-grade disease, and ▪ cervical cancer.

Mentions: To determine whether responding IFN-γ-secreting T cells in the ELISPOT were CD8+ or CD4+, peripheral blood lymphocytes were negatively depleted using magnetic beads. FACS analysis of the CD4- or CD8-depleted T-cell populations revealed that in nearly all cases there was a depletion of greater than 99% of the appropriate T-cell subset (data not shown). The results of the ELISPOT assays are shown in Figure 1 and the data are summarised in Figure 2. We demonstrated either CD4+ or CD8+ T-cell reactivity in 78% (32 out of 41) of the patient samples tested, with 34% (14 out of 41) showing both CD4 and CD8 responses (Figure 2A). Among the various disease grades, the frequency of ELISPOT responders overall was: no CIN, 83%; low-grade disease, 87.5%; high-grade disease, 69%; cervical cancer, 80% (Figure 2B).


T-cell responses to human papillomavirus type 16 among women with different grades of cervical neoplasia.

Steele JC, Mann CH, Rookes S, Rollason T, Murphy D, Freeth MG, Gallimore PH, Roberts S - Br. J. Cancer (2005)

Summary of the ELISPOT assay data. The percentages of positive ELISPOT responses obtained generally (A), in relation to disease grade (B), CD4 and CD8 responses in relation to disease grade (C), and the antigen specificities of the CD4+ and CD8+ T-cell reactivities in relation to disease grade (D). ▒ represents no CIN, □ low-grade disease, ▓ high-grade disease, and ▪ cervical cancer.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361543&req=5

fig2: Summary of the ELISPOT assay data. The percentages of positive ELISPOT responses obtained generally (A), in relation to disease grade (B), CD4 and CD8 responses in relation to disease grade (C), and the antigen specificities of the CD4+ and CD8+ T-cell reactivities in relation to disease grade (D). ▒ represents no CIN, □ low-grade disease, ▓ high-grade disease, and ▪ cervical cancer.
Mentions: To determine whether responding IFN-γ-secreting T cells in the ELISPOT were CD8+ or CD4+, peripheral blood lymphocytes were negatively depleted using magnetic beads. FACS analysis of the CD4- or CD8-depleted T-cell populations revealed that in nearly all cases there was a depletion of greater than 99% of the appropriate T-cell subset (data not shown). The results of the ELISPOT assays are shown in Figure 1 and the data are summarised in Figure 2. We demonstrated either CD4+ or CD8+ T-cell reactivity in 78% (32 out of 41) of the patient samples tested, with 34% (14 out of 41) showing both CD4 and CD8 responses (Figure 2A). Among the various disease grades, the frequency of ELISPOT responders overall was: no CIN, 83%; low-grade disease, 87.5%; high-grade disease, 69%; cervical cancer, 80% (Figure 2B).

Bottom Line: T-cell responses were observed in the majority (78%) of samples.CD8+ reactivity to E6 peptides was dominant across all disease grades, inferring that E6-specific CD8+ T cells are not vitally involved in disease clearance.Our study reveals significant differences in HPV16 immunity during progressive CIN.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. j.c.steele@bham.ac.uk

ABSTRACT
Infection with high-risk genital human papillomavirus (HPV) types is a major risk factor for the development of cervical intraepithelial neoplasia (CIN) and invasive cervical carcinoma. The design of effective immunotherapies requires a greater understanding of how HPV-specific T-cell responses are involved in disease clearance and/or progression. Here, we have investigated T-cell responses to five HPV16 proteins (E6, E7, E4, L1 and L2) in women with CIN or cervical carcinoma directly ex vivo. T-cell responses were observed in the majority (78%) of samples. The frequency of CD4+ responders was far lower among those with progressive disease, indicating that the CD4+ T-cell response might be important in HPV clearance. CD8+ reactivity to E6 peptides was dominant across all disease grades, inferring that E6-specific CD8+ T cells are not vitally involved in disease clearance. T-cell responses were demonstrated in the majority (80%) of cervical cancer patients, but are obviously ineffective. Our study reveals significant differences in HPV16 immunity during progressive CIN. We conclude that the HPV-specific CD4+ T-cell response should be an important consideration in immunotherapy design, which should aim to target preinvasive disease.

Show MeSH
Related in: MedlinePlus