The antigen-presenting environment in normal and human papillomavirus (HPV)-related premalignant cervical epithelium

Abstract

SUMMARYThe activation of HPV-specific T cells within the cervical microenvironment is likely to play an important part in the natural history of cervical intraepithelial neoplasia (CIN). The extent and the type of T cell activation will depend critically on the expression of MHC, costimulatory cell surface molecules and cytokines by keratinocytes and Langerhans cells within the cervical lesion. Expression of MHC class II (HLA-DR and -DQ), costimulatory/adhesion molecules (CD11a/18, CD50, CD54, CD58 and CD86) and cytokines (tumour necrosis factor-alpha (TNF-a) and IL-10) was therefore investigated by immunohistochemistry in normal squamous epithelium (n ¼ 12), low-grade (n ¼ 23) and high-grade (n ¼ 18) squamous intraepithelial lesions of the cervix. CIN progression was associated with de novo expression of HLA-DR and CD54, and increased expression of CD58 by keratinocytes. However, significantly, there was no expression of any adhesion/costimulation molecule by epithelial Langerhans cells in any cervical biopsy studied. Furthermore, TNF-a, a potent activator of Langerhans cells, was expressed constitutively by basal keratinocytes in normal cervix (12þ/12), but expression of this cytokine was absent in a number of CIN samples (20þ/23 for low-grade, 12þ/18 for high-grade CIN). Conversely, the suppressive cytokine IL-10 was absent in normal epithelium (0þ/12), but was upregulated in a number of CIN lesions (12þ/23 for low-grade, 8þ/18 for high-grade CIN). The restricted expression of costimulation/adhesion molecules and the nature of the cytokine microenvironment within the epithelium may act to limit effective immune responses in some CIN lesions.

Human papillomavirus type 16 E6 and E7 oncoproteins upregulate c-IAP2 gene expression and confer resistance to apoptosis

“…HPV16 E6/E7-induced activation of c-IAP2 transcription was similar to cytokine TNF-a-induced c-IAP2 activation, based on the observations that both TNF-a and HPV16 E6/E7 require the first and the third NF-kB sites in the c-IAP2 promoter (Hong et al, 2000) and the induction of c-IAP2 expression was significantly reduced in the NF-kB-deficient cell line. However, HPV16 E6/ E7-induced c-IAP2 transcription may not be mediated by TNF-a because HPV infection or E6 and E7 expression have been shown to reduce TNF-a expression in keratinocytes (Mota et al, 1999;Havard et al, 2002). Also, HPV16 E6 and E7 were reported to attenuate TNF-a-mediated NF-kB activation (Spitkovsky et al, 2002).…”

The paradox of IL-10-mediated modulation in cervical cancer

“…IL-10 levels were found to be high in almost all cervical cancer cases (28)(29)(30). However, several gene transfection studies on IL-10 have demonstrated that IL-10 has the ability to inhibit tumor growth and metastasis in several types of cancer, although the mechanisms have yet to be elucidated.…”

Human dendritic cells transfected with a human papilloma virus-18 construct display decreased mobility and upregulated cytokine production

“…Previous studies have shown that keratinocytes secrete a variety of lymphokines that are critical components of the host response to infection or injury (40,41). HPV infection may result in changes in cytokine production creating a favorable environment for viruses to evade clearance by immune cells (3,14). In this study, we found that cervical epithelial keratinocytes and HFFs support expression of viral proteins.…”

“…Tumor necrosis factor-α (TNF-α) interleukin-6 (IL-6), transforming growth factor-β (TGF-β) and monocyte chemotactic protein-1 (MCP-1) ELISA kits were purchased from Life Technologies. The selection of cytokines for this study was based upon published data suggesting their involvement in mechanisms controlling tumor growth or regression (14,30,(36)(37)(38). Transfected and non-transfected cells (10 6 cells/well) were placed in 12-well plates and grown to confluency and activated with lipopolysaccharide (1 µg/ml; LPS; Sigma Chemical Co., St. Louis, MO, USA).…”

“…For example, LC depletion might result from the creation of a locally unfavorable environment fostered by infected epithelial cells and fibroblasts. HPV-infected keratinocytes are known to express low levels of major histocompatibility complex restriction elements and do not present the necessary levels of costimulatory molecules for naive T-cell priming (14). Additionally, production of granulocyte-macrophage colony stimulating factor (GM-CSF) (15) as well as type I interferon (16,17) is significantly decreased in HPV-infected keratinocytes.…”