Interleukin-15 and Natural Killer and NKT Cells Play a Critical Role in Innate Protection against Genital Herpes Simplex Virus Type 2 Infection

Abstract

Interleukin-15 (IL-15), natural killer (NK) cells, and NK T (NKT) cells, components of the innate immune system, are known to contribute to defense against pathogens, including viruses. Here we report that IL-15−/− (NK− and NKT−/+) mice and RAG-2−/−/γc−/− (NK− and NKT−) mice that lack all lymphoid cells were very susceptible to vaginal infection with a low dose of herpes simplex virus type 2 (HSV-2). IL-15−/− and RAG-2−/−/γc−/− mice were 100-fold more susceptible and RAG-2−/−, CD-1−/− (NKT−), and gamma interferon (IFN-γ)−/− mice were 10-fold more susceptible to vaginal HSV-2 infection than control C57BL/6 mice. NK and/or NKT cells were the early source of IFN-γ in vaginal secretions following genital HSV-2 infection. This study demonstrates that IL-15 and NK-NKT cells are critical for innate protection against genital HSV-2

A Detrimental Role for Invariant Natural Killer T Cells in the Pathogenesis of Experimental Dengue Virus Infection

“…In contrast to experimental models involving other viruses, [27][28][29][30][31] iNKT cell deficiency did not lead to impaired containment and clearance of DENV in the liver and spleen in our experimental system. This finding is not without precedent because iNKT cells have been shown to be dispensable to control the virus load in some experimental systems.…”

“…Several experimental models have highlighted the beneficial role of iNKT cells in virus-associated inflammatory responses. [27][28][29][30][31][32] However, they can also contribute to the immunopathogenesis of viral diseases. For example, using an experimental mouse model of chronic lung disease triggered by infection with Sendai virus, Kim et al 33 demonstrated that IL-13 production by iNKT cells contributes to pulmonary disease.…”

“…After comparison of the phenotypes of J␣18 Ϫ/Ϫ and wild-type (WT) animals, it was reported that the role of iNKT cells during experimental viral infection can vary according to the virus and experimental conditions. 20,24 -26 For example, during infection with influenza A virus, herpes simplex virus types 1 and 2, and lymphocytic choriomeningitis virus, iNKT cells have a positive role in anti-viral immune responses and virus-associated disease, [27][28][29][30][31][32] whereas during infection with Sendai virus and herpes simplex virus type 2 (only in aged mice), iNKT cells are rather deleterious. 33,34 However, iNKT cells do not seem to participate in anti-viral immunity or control of viral replication during infection with encephalomyocarditis virus and murine cytomegalovirus.…”

Interleukin‐15 mediates protection against experimental tuberculosis: A role for NKG2D‐dependent effector mechanisms of CD8+ T cells

“…In accordance with the importance of CD8 + T cells for protection against a number of pathogens, IL-15 was shown to improve the proliferation of memory/effector CD8 + T cells and protective CD8 + T cell-mediated immune responses such as IFN-c production and cytotoxicity [37][38][39]. For example, a deficiency in IL-15 or IL-15Ra led to an impaired CD8 + T cell-mediated immune response and decreased protection from infection with herpes simplex virus type 2 [21,40], vesicular stomatitis virus (VSV) [41], vaccinia virus [18] or Toxoplasma gondii [42]. However, in some cases the role of IL-15 appeared to be redundant since IL-15 -/-mice proved capable of developing protective immune responses after infection with gamma herpes virus 68 [43], lymphocytic choriomeningitis virus [20] or T. gondii [44].…”

Viral danger signals control CD1d de novo synthesis and NKT cell activation

“…Patients with NKT cell deficiency suffer from disseminated infections with herpesviruses [10,11]. Analysis of CD1d-deficient mice revealed that in mouse models of viral infections NKT cells are required for elimination of some virus types [12][13][14][15] but not others [16][17][18][19][20]. Activated NKT cells have been found in patients with hepatitis C [21][22][23] and in a transgenic mouse model of hepatitis B virus infection [24].…”