Inhibition of NK cell activity by IL-17 allows vaccinia virus to induce severe skin lesions in a mouse model of eczema vaccinatum

Abstract

Threats of bioterrorism have renewed efforts to better understand poxvirus pathogenesis and to develop a safer vaccine against smallpox. Individuals with atopic dermatitis are excluded from smallpox vaccination because of their propensity to develop eczema vaccinatum, a disseminated vaccinia virus (VACV) infection. To study the underlying mechanism of the vulnerability of atopic dermatitis patients to VACV infection, we developed a mouse model of eczema vaccinatum. Virus infection of eczematous skin induced severe primary erosive skin lesions, but not in the skin of healthy mice. Eczematous mice exhibited lower natural killer (NK) cell activity but similar cytotoxic T lymphocyte activity and humoral immune responses. The role of NK cells in controlling VACV-induced skin lesions was demonstrated by experiments depleting or transferring NK cells. The proinflammatory cytokine interleukin (IL)-17 reduced NK cell activity in mice with preexisting dermatitis. Given low NK cell activities and increased IL-17 expression in atopic dermatitis patients, these results can explain the increased susceptibility of atopic dermatitis patients to eczema vaccinatum.

The Development of Colitogenic CD4+ T Cells Is Regulated by IL-7 in Collaboration with NK Cell Function in a Murine Model of Colitis

“…One potential interpretation is that the pathogenic T cells can continue to proliferate, resulting in induction of colitis when the T cell number exceeds the capacity of the NK cells to suppress the T cells. A second possibility is based on the recent report that IL-17 inhibits NK cell-suppressive ability (36). It has been suggested that the increased IL-17 production from T cells that occurs when the severity of the colitis increases may affect NK cell function.…”

Staphylococcal and Streptococcal Superantigen Exotoxins

“…S. aureus skin infections exacerbate skin disease in patients with AD and modify the host response to environmental allergens and viral pathogens (258,259). Recent studies suggest that host-pathogen interactions stemming from the production of S. aureus-derived virulence factors, such as superantigens and alpha-toxin, contribute greatly to the skin inflammation seen in AD (260,261).…”

Increased Protection from Vaccinia Virus Infection in Mice Genetically Prone to Lymphoproliferative Disorders

“…In light of these data suggesting that B6-lpr mice were better protected than B6 wild-type mice as early as day 2 after infection ( Fig. 2A to C, 3C and D, and 5C and D), and because other data suggested that the NK cell percentages and ␥␦ T-cell percentages were increased in B6-lpr mice infected with VACV as compared to B6 wild-type infected mice, uninfected B6-lpr and B6 mice were examined for differences in NK and ␥␦ ϩ T-cell numbers, as these lymphocytes are thought to exert effector functions early in VACV infections (6,28,35,51).…”

“…This enhanced resistance to infection was manifested as early as 2 days postinfection, when there was an elevation in the numbers of several different leukocyte populations previously shown to provide resistance to poxvirus infections: NK cells (6,12,28,35), ␥␦ ϩ T cells (51), and memory phenotype conventional ␣␤ T cells (3, 47, 52, 70). We suggest, therefore, that the heightened state of activation occurring in FAS pathway-mutant individuals might actually provide enhanced resistance to certain viral infections.…”

“…8). IFN-␥ is very important in controlling poxvirus infections (7,20,27,47,52), and separate studies have shown that VACV can be controlled by IFN-␥-producing ␥␦ ϩ T cells (51), CD8 ϩ and CD4 ϩ T cells (3,47,52,70), and NK cells (6,28,35). This suggests that several different types of leukocytes could be cooperatively or redundantly producing IFN-␥ in response to infection in B6-lpr mice, thus providing increased protection.…”