Distinct regulation and impact of type 1 T‐cell immunity against HPV16 L1, E2 and E6 antigens during HPV16‐induced cervical infection and neoplasia

Abstract

Cervical cancer is the possible outcome of a genital infection with high-risk human papillomavirus type 16 (HPV16) and is preceded by a phase of persistent HPV infection during which the host immune system fails to eliminate the virus. Our previous work showed that failure is reflected by the absence of type 1 T-cell immunity against HPV16 early antigens E2 and E6 in patients with HPV161 cervical lesions. We now show that a majority of both patients with cervical lesions and healthy subjects display HPV16 L1 peptide-specific type 1 T-cell responses with similar magnitude. The T-cell response in patients was directed at a broad range of peptides within L1, suggesting that during persistent or repeated exposure to HPV16 L1, the immune system maximizes its efforts to counter the viral challenge. Unlike the type 1 T-cell responses against HPV16 early antigens E2 and E6, type 1 T-cell immunity against L1 does not correlate with health or disease. This argues that T-cell responses against early and late HPV16 antigens essentially differ in the manner in which they are induced and regulated, as well as in their impact on the subsequent stages of HPV16-induced cervical disease. ' 2005 Wiley-Liss, Inc.Key words: HPV16; T cell; L1; VLP; cervical cancer; healthy individuals Infection of both men and women with oncogenic human papillomavirus (HPV) types, such as HPV type 16 (HPV16), is quite common 1-3 and leads to progressive disease in only a minor fraction of infected subjects. [4][5][6] The majority of the infections and HPV-induced epithelial lesions spontaneously resolve, most likely through intervention by the adaptive immune response. [7][8][9] In a majority of healthy subjects (approximately 60%) strong type 1 Tcell reactivity directed at the nonstructural proteins HPV16 E2 and E6 can be detected, [10][11][12] suggesting that these proteins are important target antigens for a protective immune response in humans, similar to what was found in animal models. [13][14][15] These animal models also revealed that L1-specific immunity can protect against infection with the cottontail rabbit papilloma virus 16 or the canine oral papilloma virus. [17][18][19] A large HPV16 L1-VLP vaccination trial in humans revealed that vaccine-induced immunity could prevent persistent HPV16 infections. 20 Although the immunologic evaluation of this trial was focused on the role of neutralizing antibodies in preventing viral infection, VLP vaccination must also have affected the underlying CD41 Th responses and possibly Th-dependent cell-mediated effector functions.Previous work has shown that patients diagnosed with HPV16 1 CIN display proliferative responses against HPV16 L1 21,22 and that there was no difference in such proliferative responses (measured by IL-2 production) between patients who cleared their lesions or in whom lesions persisted. 23 Immunity in such subjects may differ not so much in the quantitative aspects of the immune response but more in the quality of the response, as is indicated by our studies on immunity against...

Association of cervical cancer with the presence of CD4+regulatory T cells specific for human papillomavirus antigens

“…HPV16 E6-specific T cells cultured from a biopsy of the skin test site of two healthy control individuals (P02 and P08) were analyzed for proliferative capacity (A) and capacity to suppress proliferation of CD4 ϩ responder cells (B) according to procedures described in the Fig. 5 legend. HPV18, was prompted by our earlier observations that HPVpositive cervical neoplasia was associated with failure to mount an effective T cell response against these antigens (5)(6)(7)(8)(9). The presence of HPV-specific regulatory T cells at the interface of tumor and immune system, both in the tumor-draining lymph nodes and in the tumor tissue, can explain the development of immunogenic tumors in patients who do not display overt immunodeficiencies.…”

“…Indeed, HPV16 E6-, E7-, and E2-specific Th1-and Th2-type CD4 ϩ T cell responses were frequently detected in peripheral blood mononuclear cell (PBMC) cultures of healthy individuals (4-6), showing that successful defense against HPV16 infection is commonly associated with the installment of a systemic effector T cell response against these viral antigens. In contrast, PBMC cultures from patients with HPV16-positive genital lesions either lacked detectable responses against HPV16 E6, E7, and E2 or displayed antigen-specific proliferative responses exhibiting a noninflammatory cytokine profile (5,7,8). Similarly, effective HPV18-specific T cell responses are only found in healthy controls but not in HPV18-positive patients (9).…”

Skin reactions to human papillomavirus (HPV) 16 specific antigens intradermally injected in healthy subjects and patients with cervical neoplasia

“…This fits with our earlier observation that almost 50% of all cervical cancer patients do not display detectable numbers of proliferating E2, E6 and/or E7-specific T cells in their blood. [26][27][28][29] The absence of these circulating HPV-specific T cells may explain the failure to develop a skin reaction. In addition, we recently reported the involvement of regulatory T cells in cervical cancer 35,36 and one could argue that their presence may prevent the development of early or late positive skin tests.…”

“…[26][27][28][29] Based on these results, we designed a HPV16-specific skin test, consisting of the most immunogenic regions of the early proteins E2, E6 and E7, 27,29 that might be used to screen spontaneously and vaccine-induced immune responses to HPV in large groups of individuals and in areas where the access to specialized laboratories is limited. In this study, we have tested the safety and feasibility of a synthetic long peptide-based HPV16-specific skin test to detect cellular immune responses to HPV16 E2, E6 and E7 in vivo.…”

Genetic variation of antigen processing machinery components and association with cervical carcinoma

“…These subjects were nested in the CIRCLE study, which investigates cellular immunity against HPV-associated cervical lesions (van Poelgeest et al, 2006;Welters et al, 2006). The CIRCLE study design was approved by the medical ethics committee of Leiden University Medical Center.…”