HPV16E7-Induced Hyperplasia Promotes CXCL9/10 Expression and Induces CXCR3+ T-Cell Migration to Skin

Abstract

Chemokines regulate tissue immunity by recruiting specific subsets of immune cells. Mice expressing the E7 protein of human papilloma virus 16 as a transgene from a keratin 14 promoter (K14.E7) show increased epidermal and dermal lymphocytic infiltrates, epidermal hyperplasia, and suppressed local immunity. Here, we show that CXCL9 and CXCL10 are overexpressed in non-hematopoietic cells in skin of K14.E7 mice when compared with non-transgenic animals, and recruit CXCR3 lymphocytes to the hyperplastic skin. Overexpression of CXCL9 and CXCL10 is not observed in E7 transgenic mice with mutated Rb gene whose protein product cannot interact with E7 (K14.E7xRb) and in consequence lack hyperplastic epithelium. CXCR3 T cells are preferentially recruited by CXCL9 and CXCL10 in supernatants of K14.E7 but not K14.E7xRb skin cultures in vitro. CXCR3 signalling promotes infiltration of a subset of effector T lymphocytes that enables donor lymphocyte deficient, E7-expressing skin graft rejection. Taken together, this suggests that recruitment of CXCR3 T cells can be an important factor in the rejection of precancerous skin epithelium providing they can overcome local immunosuppressive mechanisms driven by skin-resident lymphocytes.

Stress keratin 17 enhances papillomavirus infection-induced disease by downregulating T cell recruitment

“…CXCR3-mediated T cell migration has been reported to be important to clear infections in other contexts, including infections by epicutaneous vaccinia virus [58], protozoan parasite Toxoplasma gondii [59], and herpes simplex virus type 2 [37]. In addition, Kuo et al found elevated CXCL9 and CXCL10 levels in cutaneous lesions arising in HPV16 E7 transgenic mice and determined that CXCR3 is critical for HPV16 E7-expressing skin graft rejection [60]. CXCR3 is a receptor expressed on activated effector CD8+ T cells, NK cells, activated Th-1 CD4+ T cells and epithelial cells.…”

Association of local immune suppression in skin with HPV-induced epithelial hyperplasia

“…K14.E7xRb ΔL/ΔL mice and non-transgenic mice have similar composition of skin-infiltrating lymphocytes (Kuo et al, 2017), and exhibit similar local immunity (Figure 3.1), as well as a similar transcriptomic profile to a non-transgenic mouse skin (Kuo et al, 2017;Zhussupbekova et al, 2016). We therefore hypothesized that E7-expressing skin lacking hyperplasia might be susceptible to immune mediated rejection.…”

“…These data demonstrate that failure of E7 transgenic skin grafts to prime an E7-specific response is not the sole reason for failure of rejection of K14.E7xRb ΔL/ΔL grafts. As E7-expression levels are similar in K14.E7 and K14.E7xRb ΔL/ΔL skin (Kuo et al, 2017), it is unlikely that the expression level of the antigen influenced the fate of K14.E7xRb ΔL/ΔL skin grafts. Thus, we hypothesized three possibilities of why the K14.E7xRb ΔL/ΔL skinThus, these grafts are tolerated-i)…”

“…Expressing comparable level of E7 transcript, the skin of K14.E7xRb ΔL/ΔL mice, whether homozygous or heterozygous for the Rb mutation, was found to closely resemble nontransgenic mouse skin (Choyce et al, 2013;Kuo et al, 2017). To test whether the local immune suppression observed in K14.E7 transgenic mouse skin was due to hyperproliferation or to some other action of E7 protein, we examined immune function in the skin of K14.E7 and K14.E7xRbΔL/ΔL mice.…”

“…K14.E7xRb ΔL/ΔL skin graft alone may not initiate sufficient skin antigen presenting cell migration and activation in the draining lymph nodes to prime T cells; ii) K14.E7xRb ΔL/ΔL skin graftseither fail to attract effector cells, consistent with their lower expression of T cell attracting chemokines (Kuo et al 2017); iii)), or E7 transgenic KC fail to present antigen effectively in the absence of the local inflammatory signals (IL-1, IL-17) that are a feature of K14.E7 skin (Tuong et al, 2018).…”