Role of innate immunity against human papillomavirus (HPV) infections and effect of adjuvants in promoting specific immune response

Abstract

During the early stages of human papillomavirus (HPV) infections, the innate immune system creates a pro-inflammatory microenvironment by recruiting innate immune cells to eliminate the infected cells, initiating an effective acquired immune response. However, HPV exhibits a wide range of strategies for evading immune-surveillance, generating an anti-inflammatory microenvironment. The administration of new adjuvants, such as TLR (Toll-like receptors) agonists and alpha-galactosylceramide, has been demonstrated to reverse the anti-inflammatory microenvironment by down-regulating a number of adhesion molecules and chemo-attractants and activating keratinocytes, dendritic (DC), Langerhans (LC), natural killer (NK) or natural killer T (NKT) cells; thus, promoting a strong specific cytotoxic T cell response. Therefore, these adjuvants show promise for the treatment of HPV generated lesions and may be useful to elucidate the unknown roles of immune cells in the natural history of HPV infection. This review focuses on HPV immune evasion mechanisms and on the proposed response of the innate immune system, suggesting a role for the surrounding pro-inflammatory microenvironment and the NK and NKT cells in the clearance of HPV infections.

Figure 1

Schematic representation of the immunological microenvironment in a human papillomavirus (HPV) infection. (a) The predominant microenvironment induced by HPV promotes a down-regulation of antigen presentation, which triggers the following phenomena: (1) modulation of the cytokine-mediated inflammatory response of keratinocytes as the first line of defense against infection; (2) the inhibition of the activation and migration of Langerhans (LCs); and (3) evasion of the infiltration of dendritic cells (DCs) from the stroma. (b) The possible pro-inflammatory microenvironment in keratinocytes adjacent to the lesion. This microenvironment is characterized by down-regulation of the anti-inflammatory cytokine IL-10 and the presence of activated T-cells. The arrows with a question mark indicate an unknown process that could reverse the HPV-induced microenvironment.

Figure 2

Schematic representation of the role of the innate immune response following adjuvant stimulation during HPV infection. (a) Stimulation of natural killer T (NKT) cells using α-GalCer, together with HPV-antigens, promotes CD4+ and CD8+ T cells antigen-specific responses and the rapid release of high levels of inflammatory cytokines, such as IFN-γ. (b) NK cells can kill HPV-infected cells, following their indirect activation through adjuvants such as α-GalCer and Toll-like receptor (TLR) agonists, via IFN-γ. (c) The induction of a pro-inflammatory response through TLR agonists rescues keratinocytes from the HPV-induced microenvironment to promote antigen presentation.