Human Dendritic Cells Are Activated by Chimeric Human Papillomavirus Type-16 Virus-Like Particles and Induce Epitope-Specific Human T Cell Responses In Vitro

Rudolf, Michael P.; Fausch, Steven C.; Silva, Diane M. Da; Kast, W. Martin

doi:10.4049/jimmunol.166.10.5917

Cited by 134 publications

(101 citation statements)

References 59 publications

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“…A prophylactic vaccine, employing HPV 16 VLPs to induce immunity, has shown promising results. 33 VLPs have been shown to be endocytosed, processed and presented by APCs to na€ ıve T cells, 34 thereby enabling class II presentation of the VLPs to activate the immune system. It is therefore likely that vaccinated women will differ in their capability to mount an effective immune response against an HPV infection, depending on their HLA class II genotype.…”

Section: Discussionmentioning

confidence: 99%

HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri

Beskow

Moberg

Gyllensten

2005

Intl Journal of Cancer

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Human papillomavirus (HPV) infection is the most important risk factor for development of cervical carcinoma. Carriers of certain HLA class II alleles, e.g., DRB1*1501 and DQB1*0602, are more prone to HPV 16 infection and cervical carcinoma, whereas other alleles, e.g., DRB1*1301 and DQB1*0603, render carriers less susceptible to the disease. In our study comprising 484 cases and 601 controls, we examine the effect of HLA class II alleles on viral load of the oncogenic types HPV 18/45 and HPV 31 and risk of developing cervical carcinoma in situ. We find that carriers of the commonly reported protective DRB1*1301 and DQB1*0603 alleles have lower HPV 18/45 load compared to noncarriers and a lower risk of developing HPV 18/45-positive cervical carcinoma. This provides further evidence that the HLA class II-mediated immune response to HPV is important for controlling viral load and outcome of an infection. ' 2005 Wiley-Liss, Inc.Key words: HLA; human papillomavirus; viral load; cervical carcinoma HPV is the major etiologic risk factor for cervical carcinoma and is found in the majority of cervical tumors. Although infection with oncogenic forms of HPV are common among young women, less than 1% of those infected develop cervical carcinoma. [1][2][3] Both the length of the infection and a high viral load several years before diagnosis have been shown to increase the risk of developing cervical dysplasia and carcinoma in situ (CIS). [4][5][6] Certain HLA class II alleles, such as DRB1*1501 and DQB1*0602, have been shown to increase the risk for cervical carcinoma, most strongly in HPV 16-positive carcinomas. [7][8][9][10][11][12][13] We have previously shown that the increased carcinoma risk primarily depends on that the alleles render carriers more susceptible to HPV16 infections. 12 In addition, carriers of these HLA susceptibility alleles had higher HPV 16 load in their cervical smears compared to HPV 16-positive noncarriers. A plausible hypothesis is that HLA is involved in the cellular immunity against HPV. Also, HLA alleles making carriers more susceptible to HPV infections are likely to be less efficient in triggering immunity and inducing viral clearance. As a consequence, carriers of susceptibility alleles harbor higher HPV load than carriers of more efficient alleles. The relation between viral load and carcinoma development has been most extensively studied for HPV 16, presumably because it is the most prevalent HPV type in cervical tumors throughout most of the world. 1 We have previously examined the effect of HPV 18/45 and HPV 31 viral load on the risk for cervical CIS. 14 Our results showed that higher viral load of HPV 18/45 or HPV 31 increases the risk of CIS, although the risk magnitude is less than that observed for HPV 16. Therefore, it is possible that HLA alleles could influence carcinoma development by affecting viral load also for other HPV types besides HPV 16.A meta analysis demonstrated a protective effect of the DRB1*1301 and DQB1*0603 alleles against development of cervical carcinoma in 18 ...

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Section: Discussionmentioning

confidence: 99%

HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri

Beskow

Moberg

Gyllensten

2005

Intl Journal of Cancer

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“…Because insect baculovirus contaminants have been reported to play a role in the immunogenicity induced by VLPs [41], we used a lysate of insect cells infected with WT baculovirus as a negative control and did not observe cytotoxic activity or cytokine production in this culture condition. As described for DC activation [42], denaturated VLPs were not able to activate NK cells. To further characterize the intracellular mechanisms induced by VLPs, we will investigate the role of MAP kinases that have been implicated in NK-cell degranulation or in ADCC after CD16 triggering [43,44].…”

Section: Cells But Not In Nk92 Cd16mentioning

confidence: 99%

Human papillomavirus entry into NK cells requires CD16 expression and triggers cytotoxic activity and cytokine secretion

et al. 2011

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Human papillomavirus (HPV) infections account for more than 50% of infection-linked cancers in women worldwide. The immune system controls, at least partially, viral infection and around 90% of HPV-infected women clear the virus within two years. However, it remains unclear which immune cells are implicated in this process and no study has evaluated the direct interaction between HPVs and NK cells, a key player in host resistance to viruses and tumors. We demonstrated an NK-cell infiltration in HPVassociated preneoplastic cervical lesions. Since HPVs cannot grow in vitro, virus-like particles (VLPs) were used as a model for studying the NK-cell response against the virus. Interestingly, NK cells displayed higher cytotoxic activity and cytokine production (TNF-a and IFN-c) in the presence of HPV-VLPs. Using flow cytometry and microscopy, we observed that NK-cell stimulation was linked to rapid VLP entry into these cells by macropinocytosis. Using CD16 1 and CD16 À NK-cell lines and a CD16-blocking antibody, we demonstrated that CD16 is necessary for HPV-VLP internalization, as well as for degranulation and cytokine production. Thus, we show for the first time that NK cells interact with HPVs and can participate in the immune response against HPV-induced lesions. IntroductionHigh-risk human papillomaviruses (HPVs) are the causative agents of uterine cervical cancer and are also etiologically associated with other anogenital tumors and with head and neck carcinomas [1].Among the 100 HPV genotypes already characterized, 15 are oncogenic and more than 50% of uterine cervical cancers are associated with HPV16 [2]. Because of their keratinocyte differentiation-dependent life cycle, virus production in vitro has required complex cell culture systems and only low virus titers can be obtained [3]. Consequently, most studies aiming to investigate interactions between virus and host cells have used virus-like particles (VLPs), which result from HPV L1 major capsid protein self-assembly and which are morphologically and immunologically [5,6]. Yet, these vaccines have no therapeutic efficacy and it has been estimated that there will be no measurable decline of HPVassociated tumors before 2040 [7].HPV infection can be controlled by the host immune response and the vast majority of HPV-infected women clear the virus within two years [8]. Moreover, the prevalence of HPV-induced tumors is higher in immunodeficient patients [9]. However, it remains unclear which immune cells are implicated in this process and no study has been performed evaluating the direct interaction between HPVs and NK cells, although these cells play a key role in host resistance to viruses [10] (Fig. 1A and B), but not in squamous cell carcinoma (SCC) (Fig. 1D) despite the presence of more numerous NK cells in the surrounding stroma (Supporting Information Fig. 1). Interestingly, virus particles have been detected mainly in SILs and not in SCC [19] where the virus is usually integrated into the host genome [20]. Our results thus suggest that NK cells could...

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“…It was found previously that HPV16 L1 VLP interact with and activate multiple cells of the immune system including monocyte-derived DC (mDC), monocytes and macrophages, providing an experimental explanation for their immunogenicity [19][20][21]. Furthermore, mDC, but not epidermal Langerhans cells, have been shown to present VLP-derived antigenic determinants to primary T cells [19,20,22]. However, it is not known whether pDC share this ability to respond to papillomavirus VLP.…”

Section: Introductionmentioning

confidence: 99%

“…These characteristics have made HPV16 L1 VLP an attractive candidate for prophylactic subunit vaccines currently in human clinical trials for long-term protection against naturally transmitted papillomavirus infection and its pathologies, including cervical cancer [17,18]. It was found previously that HPV16 L1 VLP interact with and activate multiple cells of the immune system including monocyte-derived DC (mDC), monocytes and macrophages, providing an experimental explanation for their immunogenicity [19][20][21]. Furthermore, mDC, but not epidermal Langerhans cells, have been shown to present VLP-derived antigenic determinants to primary T cells [19,20,22].…”

Section: Introductionmentioning

confidence: 99%

Papillomavirus virus‐like particles induce cytokines characteristic of innate immune responses in plasmacytoid dendritic cells

Lenz¹,

Lowy²,

Schiller³

2005

Eur J Immunol

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Human papillomavirus (HPV) virus-like particles (VLP) are being extensively tested as vaccines for the prevention of HPV-associated cervical cancer. Dendritic cells (DC) acquire and present antigens, initiating innate and adaptive immune responses. It has been shown previously that DC of the myeloid lineage are capable of generating adaptive immune responses to HPV VLP in vitro. However, the capacity of plasmacytoid DC (pDC) to acquire HPV VLP and the nature of the immune response generated have not been reported. In this study we found that freshly isolated as well as CpG-matured pDC bind papillomavirus VLP and that internalization occurs preferentially in the immature pDC. In contrast to myeloid DC, pDC did not undergo phenotypic maturation upon exposure to HPV16 VLP. However, HPV16 VLP induced pDC to secrete of IFN-a and IL-6, both cytokines that play a role in the generation of antibody responses, as well as TNFa and IL-8. Given that VLP do not contain viral nucleic acids, these results indicate that viral capsids alone may be capable of inducing cytokine production by pDC. Finally, CpG-activated pDC, but not pDC exposed to HPV16 VLP, activated lymphocytes to secrete IL-10 and low levels of IFN-c. Together these findings suggest a possible immunogenic effect of pDC in the setting of VLP vaccination.

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Human Dendritic Cells Are Activated by Chimeric Human Papillomavirus Type-16 Virus-Like Particles and Induce Epitope-Specific Human T Cell Responses In Vitro

Cited by 134 publications

References 59 publications

HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri

HLA class II allele control of HPV load in carcinoma in situ of the cervix uteri

Human papillomavirus entry into NK cells requires CD16 expression and triggers cytotoxic activity and cytokine secretion

Papillomavirus virus‐like particles induce cytokines characteristic of innate immune responses in plasmacytoid dendritic cells

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