Inhibition of NK cell activity by IL-17 allows vaccinia virus to induce severe skin

Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 07/2009; 206(6):1219-25. DOI: 10.1084/jem.20082835
Source: PubMed


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.

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Available from: Kenji Yumoto, Oct 10, 2015
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    • "IL-17A promotes the mobilization and cytotoxity of hepatic NK cells. Recently, Kawakami et al has reported that IL-17A inhibits skin NK cell's activity in a mouse model of atopic dermatitis, which was apparently at odds with our reports [37]. However, in that eczema vaccinatum model, skin NK cells were activated in a IL-4 dependent way, while in Poly I:C-induced hepatitis, hepatic NK cells were activated by Poly I:C directly and the inflammatory cytokines IL-12 and type I IFN [38], [39], [40], [41]. "
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    ABSTRACT: Immune-mediated responses were the main causes of liver damage during viral hepatitis, and recently viral RNA mimetic Poly I:C was used to induce a NK cell-dominated acute hepatitis. Interleukin-17A (IL-17A), the cytokine tightly associated with various autoimmune diseases, was known to play protective or pathological roles in LPS and ConA-induced hepatitis. However, its role in NK cell-mediated acute hepatitis remains unknown. Here we demonstrated that Poly I:C treatment triggered IL-17A production from hepatic γδT cells. Neutralizing IL-17A by monoclonal antibodies reduced Poly I:C-induced intrahepatic inflammatory responses and the liver injury through decreased accumulation, activation and cytolytic activity of NK cells in the liver. Furthermore, Poly I:C didn't trigger IL-17A secretion from γδT cells directly, and Kuppfer cells were demonstrated to be the accessory cell that can secrete IL-23. Finally, our findings demonstrated a pathological role of IL-17A and γδT cells in Poly I:C-induced acute hepatitis, which provides novel insights into viral infection-induced hepatitis and may serve as potential target in clinic immunotherapy against these disease.
    PLoS ONE 09/2013; 8(9):e73909. DOI:10.1371/journal.pone.0073909 · 3.23 Impact Factor
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    • "IL - 17 secreting Th cells ( Th17 ) have been implicated in promoting inflammation responsible for immunopathology in both cancer and several autoimmune disorders . Studies in various murine tumor models have suggested that Th17 cells may be associated with tumor initiation and growth in the context of chronic inflam - mation ( Kawakami et al . , 2009 ; Wang et al . , 2009 ; Wu et al . , 2009b ) ."
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    ABSTRACT: The importance of CD4 T cells in orchestrating the immune system and their role in inducing effective T cell-mediated therapies for the treatment of patients with select established malignancies are undisputable. Through a complex and balanced array of direct and indirect mechanisms of cellular activation and regulation, this functionally diverse family of lymphocytes can potentially promote tumor eradication, long-term tumor immunity, and aid in establishing and/or rebalancing immune cell homeostasis through interaction with other immune cell populations within the highly dynamic tumor environment. However, recent studies have uncovered additional functions and roles for CD4 T cells, some of which are independent of other lymphocytes, that can not only influence and contribute to tumor immunity but paradoxically promote tumor growth and progression. Here, we review the recent advances in our understanding of the various CD4 T cell lineages and their signature cytokines in disease progression and/or regression. We discuss their direct and indirect mechanistic interplay among themselves and with other responding cells of the antitumor response, their potential roles and abilities for "plasticity" and memory cell generation within the hostile tumor environment, and their potentials in cancer treatment and immunotherapy.
    Frontiers in Oncology 03/2013; 3:63. DOI:10.3389/fonc.2013.00063
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    • "In addition, the importance of NK cells to the response in the skin has also been suggested through studies in a mouse model of the deviated response to vaccinia virus in eczema patients. In a mouse strain that is eczema-prone (NC/Nga mice), local IL-17 limits the NK response in the skin leading to the uncontrolled viral replication and severe erosive lesions similar to the problems associated with vaccinia virus vaccination in humans with eczema (Kawakami et al., 2009). "
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    ABSTRACT: In recent years, our understanding of the role of natural killer (NK) cells in the response to viral infection has grown rapidly. Not only do we realize viruses have many immune-evasion strategies to escape NK cell responses, but that stimulation of NK cell subsets during an antiviral response occurs through receptors seemingly geared directly at viral products and that NK cells can provide a memory response to viral pathogens. Tremendous knowledge has been gained in this area through the study of herpes viruses, but appreciation for the significance of NK cells in the response to other types of viral infections is growing. The function of NK cells in defense against poxviruses has emerged over several decades beginning with the early seminal studies showing the role of NK cells and the NK gene complex in susceptibility of mouse strains to ectromelia, a poxvirus pathogen of mice. More recently, greater understanding has emerged of the molecular details of the response. Given that human diseases caused by poxviruses can be as lethal as smallpox or as benign as Molluscum contagiosum, and that vaccinia virus, the prototypic member of the pox family, persists as a mainstay of vaccine design and has potential as an oncolytic virus for tumor therapy, further research in this area remains important. This review focuses on recent advances in understanding the role of NK cells in the immune response to poxviruses, the receptors involved in activation of NK cells during poxvirus infection, and the viral evasion strategies poxviruses employ to avoid the NK response.
    Frontiers in Immunology 01/2013; 4:7. DOI:10.3389/fimmu.2013.00007
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