Evaluation of Immunological Cross‐Reactivity between Clade A9 High‐Risk Human Papillomavirus Types on the Basis of E6‐Specific CD4⁺Memory T Cell Responses

Abstract

CD4(+) T cell responses against the E6 oncoprotein of human papillomavirus (HPV) type 16 and 5 closely related members of clade A9 (HPV31, 33, 35, 52, and 58) were charted in peripheral blood mononuclear cell cultures from healthy subjects and patients who underwent HPV16 E6/E7-specific vaccination. Initial analyses with overlapping peptide arrays showed that approximately one-half of the responding subjects displayed reactivity against corresponding E6 peptides from >or=2 HPV types. This suggested immunological cross-reactivity and complicated retrospective evaluation of the infection history of the healthy subjects. Importantly, further dissection of the response by means of enriched and clonal T cell cultures (with protein antigen instead of peptides) revealed that CD4(+) T cells that are capable of efficiently reacting against E6 antigen from multiple HPV types are rare and only occur when epitope sequences are highly conserved. Our data indicate that natural and vaccine-induced HPV16 E6-specific CD4(+) T cell responses are unlikely to mediate efficient cross-protection against other clade A9 members.

Human papillomavirus 16 E2-, E6- and E7-specific T-cell responses in children and their mothers who developed incident cervical intraepithelial neoplasia during a 14-year follow-up of the Finnish Family HPV cohort

“…Previously we reported that there are highly conserved domains in HPV E2 protein sequence among different HPV genotypes, which could lead to cross-reactivity between the E2 peptides of different types of HPV [13,14]. However, cross-reactive T cells to HPV16 E6 are rare [40] suggesting that the responses observed in these children most likely reflect true circulating HPV16-specific memory T-cells during their early childhood. The authors consider that rather perplexing, because all these children were sexually inexperienced.…”

The presence of human papillomavirus (HPV) in placenta and/or cord blood might result in Th2 polarization

“…Furthermore, a cross-reactivity of HPV16 E2, E6, and E7 peptides with T-cells specific to other closely related HPV types is conceivable, albeit a rarely observed event [3, 4, 33, 40]. …”

Th2 type inflammation promotes the gradual progression of HPV-infected cervical cells to cervical carcinoma

“…Invasive cervical cancer (ICC) provides an ideal system to investigate the relation of immunological mechanisms to tumor etiology and progression. The etiological agent, high risk human papillomavirus (hr-HPV), is known [7], its E6 and E7 genes encode tumor specific epitopes that can be recognized by immune T lymphocytes to cause cell destruction [8-11], and expression of these epitopes is intimately associated with the neoplastic transformation [12], a situation similar to that in rodent tumors caused by the polyoma virus, where neoplastic variants lacking the virus encoded cellular antigen could not be isolated by immunoselection [13]. Furthermore, the lesions preceding ICC are well defined, including cervical intraepithelial neoplasia (CIN) grades 1, 2, and CIN3/carcinoma in situ (CIS) [14-18], and archived cervical samples are available from women at different stages of the disease.…”