Human Papillomavirus Virus-Like Particles Do Not Activate Langerhans Cells: A Possible Immune Escape Mechanism Used by Human Papillomaviruses

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

doi:10.4049/jimmunol.169.6.3242

Cited by 122 publications

(145 citation statements)

References 48 publications

Supporting

Mentioning

133

Contrasting

Unclassified

Order By: Relevance

“…In addition, a strong T cell response to L1-VLP was observed when T cells were co-cultured with L1-VLPpulsed autologous DC (average of 15-fold increase over response to DC pulsed with medium, p = 0.008, n = 6). These results are in agreement with previous studies [28]. Since DC-SIGN appeared to be involved in activation of MHC class I antigen and cytokine responses in DC, we examined the effect of DC pulsed with L1-VLP in the The proliferative response of purified T cells after incubation with DC pulsed with L1-VLP in the presence of anti-DC-SIGN antibodies was higher, although not statistically significant, than with DC incubated with VLP alone (approximately 35% increase).…”

Section: Blocking the Interaction Of L1-vlp With Dc-sign Inhibits Vlpsupporting

confidence: 94%

See 1 more Smart Citation

Role of DC‐SIGN in the activation of dendritic cells by HPV‐16 L1 virus‐like particle vaccine

et al. 2006

View full text Add to dashboard Cite

Dendritic cell-specific intercellular adhesion molecule-grabbing non-integrin (DC-SIGN), a specific C-type lectin expressed on DC, binds and transmits different pathogens to susceptible cells. In the present study, we examined the role of DC-SIGN in the capture of human papillomavirus (HPV) pseudovirions and activation of DC. We demonstrate that HPV virus-like particles (VLP) bind to DC-SIGN expressed on transfected Raji cells and that antibodies against DC-SIGN block this interaction. DC take up VLP, which activate expression of costimulatory markers and cytokines/ chemokines. Although our results indicate that DC-SIGN is not the major receptor for VLP in DC, this interaction contributes to the activation of DC surface antigens (HLA class I) and of various cytokines/chemokines, particularly TNF-a, IL-6, and RANTES. Induction of these markers in DC by VLP was significantly abrogated when binding to DC-SIGN was blocked by anti-DC-SIGN antibodies. These results suggest that DC-SIGN has a functional role in DC activation induced by HPV-16 L1-VLP, and thus highlight new aspects of DC interactions with HPV VLP. IntroductionThe C-type lectin dendritic cell-specific intercellular adhesion molecule-grabbing non-integrin (DC-SIGN; CD209) is a pathogen recognition receptor that interacts with mannose residues of glycoproteins in a calciumdependent manner via its C-terminal carbohydrate recognition domain [1,2]. DC-SIGN acts both as an adhesion molecule and pathogen recognition receptor, facilitating DC binding and internalization of several viruses, including HIV-1 [3].In addition to HIV, DC-SIGN was recently shown to bind a variety of microorganisms such as CMV [4], Ebola virus [5], Dengue virus [6], hepatitis C virus [7,8], simian immunodeficiency virus [9], Leishmania [10], Candida albicans [11], Mycobacterium [12][13][14] and Schistosoma [15]. Some pathogens subvert DC functions to escape immune surveillance [16]. DC-SIGN is abundantly expressed primarily on DC, including those derived from monocytes and those located beneath the genital surface [3].Human papillomavirus (HPV) virus-like particles (VLP) are a promising vaccine candidate for HPV and cervical cancer [17][18][19][20]. Recent clinical trials have shown that VLP afford excellent protection against persistent infection [20,21]. Because of the lack of a suitable cell culture system for in vitro propagation of HPV and the unavailability of virions, HPV VLP have been used as soluble surrogates for native virus particles. The routes of HPV-16 L1-VLP entry in DC and the nature of cellular receptors involved in capture have been studied but remain to be fully characterized. HPV VLP Here, we report that HPV-16 L1-VLP particles bind to DC-SIGN in transfected cell lines, and to a lesser extent in DC, and that this interaction participates in L1-VLPinduced activation of DC. Thus, DC-SIGN is likely involved in DC activation by HPV VLP. Results and discussion HPV L1-VLP bind to DC-SIGN in DC-SIGN-transfected cell linesTo study interactions between L1-VLP and DC-SIGN, we...

show abstract

Section: Blocking the Interaction Of L1-vlp With Dc-sign Inhibits Vlpsupporting

confidence: 94%

Section: Blocking the Interaction Of L1-vlp With Dc-sign Inhibits Vlpsupporting

confidence: 94%

Role of DC‐SIGN in the activation of dendritic cells by HPV‐16 L1 virus‐like particle vaccine

et al. 2006

View full text Add to dashboard Cite

show abstract

“…It is cleaved via reaction with intracellular esterases into a highly reactive fluorochrome that can be detected by flow cytometry using excitation at 488 nm and the fluorescence 1 detection channel. Thus, fluorescence intensity correlates with the amount of internalized CFSE-labeled VLP [22]. As seen in Fig.…”

Section: Binding and Internalization Of Papillomavirus Vlp By Pdcmentioning

confidence: 71%

“…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%

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

Lenz¹,

Lowy²,

Schiller³

2005

Eur J Immunol

View full text Add to dashboard Cite

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.

show abstract

“…Research on VLP interactions with dendritic cell types have shown that epithelial dendritic cells that are located at the site of natural HPV infection, the Langerhans cells (LC), do not get activated when incubated with VLP and do not initiate epitope-specific immune responses against VLP-derived antigens. 89 This is because LC present HPVderived peptides in the absence of costimulation, thereby becoming immune-suppressive. 90 On the other hand, myeloid dendritic cells are activated by VLP and once activated, they are able to stimulate HPV-specific T cells.…”

Section: Immune Response Modifiersmentioning

confidence: 99%

Recent advances in strategies for immunotherapy of human papillomavirus‐induced lesions

Kanodia

Silva

Kast

2007

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

Human papillomavirus (HPV)-induced lesions are distinct in that they have targetable foreign antigens, the expression of which is necessary to maintain the cancerous phenotype. Hence, they pose as a very attractive target for ''proof of concept'' studies in the development of therapeutic vaccines. This review will focus on the most recent clinical trials for the immunotherapy of mucosal and cutaneous HPV-induced lesions as well as emerging therapeutic strategies that have been tested in preclinical models for HPVinduced lesions. Progress in peptide-based vaccines, DNA-based vaccines, viral/bacterial vector-based vaccines, immune response modifiers, photodynamic therapy and T cell receptor based therapy for HPV will be discussed. ' 2007 Wiley-Liss, Inc.Key words: human papillomavirus; immunotherapy; therapeutic vaccines; immunomodulation; animal models; clinical trialsThe human papillomaviruses (HPVs) are a family of sexually transmitted, double-stranded DNA viruses with over 100 different genotypes identified till date. HPV genotypes are divided into the low-risk and high-risk categories based on the spectrum of lesions they induce. Fifteen HPV types are classified as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73 and 82); 3 are classified as probable high-risk types (26, 53 and 66) and 12 are classified as low-risk types (6,11,40,42,43,44,54,61,70,72, 81 and CP6108). 1 The low-risk types primarily induce benign genital condylomas and low-grade squamous intraepithelial lesions whereas the high-risk types are most frequently associated with the development of anogenital cancers and can be detected in 99% of cervical cancers, 2 with HPV16 found in about 50% of cases. 3 Infection by the low-risk types is not confined to the anogenital area and can cause other diseases such as recurrent respiratory papillomatosis. Similarly, infection by the high-risk types is also not confined to the anogenital area, since 18.3% of cancers of the oropharynx contain DNA from these types. 4 In the United States, an estimated 75% of the sexually active general population ages 15-49 years acquires at least one genital HPV type during their lifetime. 5 Though most individuals remain asymptomatic and spontaneously clear their infections, a small percentage of patients develop clinically or histologically recognizable lesions that develop into invasive cancer. The widespread use of cervical cytological screening using Papanicolaou (Pap) smear tests has reduced the mortality rate from cervical cancer in developed countries. However, in developing countries where screening programs are minimal, cervical cancer remains the second leading cause of cancer-related deaths among women. 6 Furthermore, Pap smear tests will not help identify HPV infection in males, where it can cause penile and anal cancers as well as cancers of the head and neck. Thus, it is essential to develop effective prophylactic and therapeutic strategies directed against HPV. Prophylactic vaccinesWhile therapeutic vaccines aim to develop a strong ...

show abstract

Human Papillomavirus Virus-Like Particles Do Not Activate Langerhans Cells: A Possible Immune Escape Mechanism Used by Human Papillomaviruses

Cited by 122 publications

References 48 publications

Role of DC‐SIGN in the activation of dendritic cells by HPV‐16 L1 virus‐like particle vaccine

Role of DC‐SIGN in the activation of dendritic cells by HPV‐16 L1 virus‐like particle vaccine

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

Recent advances in strategies for immunotherapy of human papillomavirus‐induced lesions

Contact Info

Product

Resources

About