[Show abstract][Hide abstract] ABSTRACT: Type I interferons (IFNs) are critical for controlling pathogenic virus infections and can enhance immune responses. Hence their impact on the effectiveness of live-attenuated vaccines involves a balance between limiting viral antigen expression and enhancing the development of adaptive immune responses. We examined the influence of type I IFNs on these parameters following immunization with RepliVAX WN, a single-cycle flavivirus vaccine (SCFV) against West Nile virus (WNV) disease. RepliVAX WN-immunized mice produced IFN-α and displayed increased IFN-stimulated gene transcription in draining lymph nodes (LN). SCFV gene expression was over 100 fold-higher on days 1-3 post-infection in type I IFN receptor knockout mice (IFNAR(-/-)) compared to wild-type (wt) mice indicating a profound IFN-mediated suppression of SCFV gene expression in the wt animals. IFNAR(-/-) mice produced nearly equivalent levels of WNV-specific serum IgG and WNV-specific CD4(+) T cell responses compared to wt mice. However, significantly higher numbers of WNV-specific CD8(+) T cells were produced by IFNAR(-/-) mice and a significantly greater percentage of these T cells from IFNAR(-/-) mice produced only IFN-γ following antigen-specific re-stimulation. This altered cytokine expression was not associated with increased antigen load suggesting the loss of type I IFN receptor signaling was responsible for the altered quality of the CD8(+) effector T cell response. Together, these results indicate that although type I IFN is not essential for the intrinsic adjuvanting of RepliVAX WN, it plays a role in shaping the cytokine secretion profiles of CD8(+) effector T cells elicited by this SCFV.
[Show abstract][Hide abstract] ABSTRACT: CD8(+) T cells are important for resolution of HSV-2 lesions from the female genital epithelium. It is uncertain whether optimal clearance of viruses such as HSV-2 that cause a limited, non-systemic infection solely requires expression of effector functions by infiltrating CD8(+) T lymphocytes, or if the clearance rate is reflective of the expression level of critical effector functions. To address this, CD8(+) T cells from normal OT-I mice or OT-I mice deficient in IFNγ (IFNγ(-/-)) or the IFNγ receptor (IFNγR(-/-)) were activated in vitro in the presence of IFNγ or IL-4 to generate a series of effector populations (Tc1 and Tc2-like respectively) that secreted different levels of IFNγ and expressed different levels of HSV-specific cytolytic function. Compared with Tc1 cells, Tc2-like cells produced the type 2 cytokines IL-4 and IL-5, exhibited decreased IFNγ secretion, diminished proliferation in vitro, and decreased antigen-specific cytolysis in vivo. Clearance of an ovalbumin-expressing HSV-2 strain (HSV-2 tk(-) OVA) by adoptively transferred Tc2-like cells was delayed relative to Tc1 cell recipients. Because donor Tc2-like cells proliferated in vivo and infiltrated the infected genital epithelium similar to Tc1 cells, the diminished virus clearance by Tc2-like effector cells correlated with reduced expression of critical effector functions. Together, these results suggest that high level expression of protective T cell functions by effector T cells is necessary for optimal clearance of HSV-2 from the genital epithelium. These results have important implications for vaccines designed to elicit CD8(+) T cells against viruses such as HSV-2 that infect the genital tract.
Journal of Reproductive Immunology 03/2011; 89(1):10-7. · 2.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We recently reported that immunization with RepliVAX WN, a single-cycle West Nile virus (WNV) vaccine, protected mice against WNV challenge. We have extended these studies by characterizing the RepliVAX WN-elicited antibody and T cell responses. WNV-specific IgG antibody responses comprised predominantly of IgG(2c) and IgG(2b) subclasses were detected 8 months after immunization. Vigorous WNV-specific CD4(+) and CD8(+) T cell responses directed at both structural and nonstructural WNV proteins were detected which were characterized by cytolytic activity and secretion of IFN-γ and TNF-α. Importantly, RepliVAX WN immunization resulted in vigorous CD8(+) memory T cell responses detected at 8 months after immunization.
[Show abstract][Hide abstract] ABSTRACT: Interferon gamma (IFNgamma) is important for immune resistance to herpes simplex virus (HSV) infection. To examine the influence of IFNgamma on the development of HSV-specific immune responses and test for IFNgamma-independent adaptive immune mechanisms of protection, IFNgamma-deficient mice (IFNgamma(-/-)) were immunized with thymidine kinase-deficient HSV-2 (HSV-2 333tk(-)). HSV-specific cellular and humoral responses were elicited in immunized IFNgamma(-/-) mice resulting in increased resistance relative to non-immune C57BL/6J (B6) mice following challenge with fully virulent HSV-2. CD8(+) T cells from IFNgamma(-/-) mice displayed cytotoxic activity and secreted TNFalpha. HSV-specific CD4(+) T cells from immunized IFNgamma(-/-) mice secreted IL-4, TNFalpha, and IL-17, but unlike T cells from HSV-immune B6 mice, could not clear virus from genital tissue following adoptive transfer. HSV-immune IFNgamma(-/-) mice produced predominantly IgG(1) HSV-specific antibodies while immune B6 mice produced predominantly IgG(2c) antibodies. Transfer of equivalent amounts of HSV-specific antibodies from either strain to naïve mice imparted equivalent early resistance against infection of the genital epithelia. However, protection against neurological symptoms mediated by immune B6 antibodies was superior late in infection. Taken together, these results demonstrate that the limited resistance of HSV-immune IFNgamma(-/-) mice to HSV-2 infection resulted from the action of HSV-specific Ab rather than IFNgamma-independent effector functions of T cells. Further, protection against neurological manifestations of HSV-2 infection was superior in mice receiving Ab from immune B6 mice suggesting that Ab-mediated protective mechanisms involving IFNgamma-induced IgG subclasses were more effective once virus had spread to neural tissues.
Journal of Reproductive Immunology 11/2009; 84(1):8-15. · 2.34 Impact Factor