Strain-Specific Properties and T Cells Regulate the Susceptibility to Papilloma Induction by Mus musculus Papillomavirus 1

Abstract

The immunocytes that regulate papillomavirus infection and lesion development in humans and animals remain largely undefined. We found that immunocompetent mice with varying H-2 haplotypes displayed asymptomatic skin infection that produced L1 when challenged with 6×1010 MusPV1 virions, the recently identified domestic mouse papillomavirus (also designated “MmuPV1”), but were uniformly resistant to MusPV1-induced papillomatosis. Broad immunosuppression with cyclosporin A resulted in variable induction of papillomas after experimental infection with a similar dose, from robust in Cr:ORL SENCAR to none in C57BL/6 mice, with lesional outgrowth correlating with early viral gene expression and partly with reported strain-specific susceptibility to chemical carcinogens, but not with H-2 haplotype. Challenge with 1×1012 virions in the absence of immunosuppression induced small transient papillomas in Cr:ORL SENCAR but not in C57BL/6 mice. Antibody-induced depletion of CD3+ T cells permitted efficient virus replication and papilloma formation in both strains, providing experimental proof for the crucial role of T cells in controlling papillomavirus infection and associated disease. In Cr:ORL SENCAR mice, immunodepletion of either CD4+ or CD8+ T cells was sufficient for efficient infection and papillomatosis, although deletion of one subset did not inhibit the recruitment of the other subset to the infected epithelium. Thus, the functional cooperation of CD4+ and CD8+ T cells is required to protect this strain. In contrast, C57BL/6 mice required depletion of both CD4+ and CD8+ T cells for infection and papillomatosis, and separate CD4 knock-out and CD8 knock-out C57BL/6 were also resistant. Thus, in C57BL/6 mice, either CD4+ or CD8+ T cell-independent mechanisms exist that can protect this particular strain from MusPV1-associated disease. These findings may help to explain the diversity of pathological outcomes in immunocompetent humans after infection with a specific human papillomavirus genotype.

Absence of γ-Chain in Keratinocytes Alters Chemokine Secretion, Resulting in Reduced Immune Cell Recruitment

“…Together, the data show that activation of keratinocytes by IL-15 is sufficient to induce recruitment of neutrophils. Because neutrophils are not thought to be associated with protection against HPV, we tested the response of DCs and CD4 + T cells that are considered to be more relevant during HPV infection (Amador-Molina et al, 2013; Handisurya et al, 2013, 2014; Wang et al, 2015). As seen with neutrophils, the average speed of DC migration in two-dimensional chambers (Figure 5a) was significantly increased using the chemokine cocktail at the concentrations released by IL-15–stimulated control keratinocytes (“scr + IL-15” in Figure 5b–d).…”

“…This, however, does not explain why established wart lesions fail to regress in γc-deficiency despite restoration of T-cell immunity that is considered the major factor for immunological control of established HPV infection (Coleman et al, 1994; Handisurya et al, 2014; Knowles et al, 1996; Nicholls et al, 2001; Uberoi et al, 2016; Wilgenburg et al, 2005). …”

“…We propose that this could create a favorable environment for viral infection and subsequent formation of wart lesions by impairing the early immune response. In addition, the ability to induce CD4 + T-cell recruitment, known to be important for wart regression in animal models and humans (Coleman et al, 1994; Handisurya et al, 2014; Nicholls et al, 2001; Peng et al, 2007; Wilgenburg et al, 2005), was impaired in response to established infection in γc-deficient keratinocytes, which could be a factor favoring persistence of warts. We propose a model in which γc-deficiency limited to keratinocytes alters the host response both at the onset and in the persistence of HPV infection (see Supplementary Figure S4 online).…”

Evasion of host immune defenses by human papillomavirus

“…A recent study has shown that LCs isolated from women with persistent HPV16 infection can present HPV antigens and activate HPV16-specific CD8 + T cells (Da Silva et al, 2015). Additionally, using the recently established mouse papillomavirus (Mus musculus papillomavirus 1 or MmuPV1) model, Handisurya et al revealed that productive MmuPV1 infection and papilloma formation require both CD4 + and CD8 + T cell functions; while CD4- or CD8-knockout C57BL/6 mice were resistant to productive MmuPV infection, depletion of CD4 + and CD8 + T cells from immunocompetent mice led to infection and papilloma formation (Handisurya et al, 2014). In addition, UVB irradiation-induced systemic immune suppression causes mice to become highly susceptible to MmuPV1 infection, which ultimately results in the development of squamous cell carcinoma (Uberoi et al, 2016).…”

Recent advances in preclinical model systems for papillomaviruses

“…Most mouse strains are susceptible to infection in which adaptive immunity plays a major role in rapid clearance (Handisurya, Day et al, 2014; Wang, Jiang et al, 2015; Sundberg, Stearns et al, 2014). …”