Herpes simplex virus (HSV)-specific T cells activated in the absence of IFN-gamma express alternative effector functions but are not protective against genital HSV-2 infection.

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. 2009 Elsevier Ireland Ltd. All rights reserved.