Modulation of antigen presenting cell functions during chronic HPV infection

Abstract

High-risk human papillomaviruses (HR-HPV) infect basal keratinocytes, where in some individuals they evade host immune responses and persist. Persistent HR-HPV infection of the cervix causes precancerous neoplasia that can eventuate in cervical cancer. Dendritic cells (DCs) are efficient in priming/cross-priming antigen-specific T cells and generating antiviral and antitumor cytotoxic CD8+ T cells. However, HR-HPV have adopted various immunosuppressive strategies, with modulation of DC function crucial to escape from the host adaptive immune response. HPV E6 and E7 oncoproteins alter recruitment and localization of epidermal DCs, while soluble regulatory factors derived from HPV-induced hyperplastic epithelium change DC development and influence initiation of specific cellular immune responses. This review focuses on current evidence for HR-HPV manipulation of antigen presentation in dendritic cells and escape from host immunity.

Fig. 1

Schematic illustration of tumor -infiltrating T cell interactions with dendritic cells. Chronic IFN-γ secretion from tumor infiltrating cells and cell to cell interaction through CTLA-4 on T_reg cells with CD80/CD86 on DCs induce IDO expression and activities. The increased activity of IDO inhibits effector function of T cells through depleting tryptophan and increased kynurenine catabolite, kynurenine. Increase production of the immune inhibitory molecules IL-10, TGF-β and CTLA-4 in T_reg cells downregulate maturation of DCs. Ligation of TCR with cognate peptide-loaded MHC molecules on dendritic cells that lack the co-stimulatory surface markers and/or PD-1-PD-L1 interactions lead to T cell proliferation arrest or anergy. APC: antigen presenting cell; IDO-1: Indoleamine 2, 3-dioxygenase; IL-10: interlunkin-10; IFN-γ: Interferon γ; IFN-γ-R: IFN-γ receptor; CTLA-4: cytotoxic lymphocyte-associated antigen-4; TCR: T cell receptor; PD-1/PD-L1: programmed death receptor 1/programmed death ligand 1; TGF-β: Tumor growth factor β.