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 (IFN gamma) is important for immune resistance to herpes simplex virus (HSV) infection. To examine the influence of IFN gamma on the development of HSV-specific immune responses and test for IFN gamma-independent adaptive immune mechanisms of protection, IFN gamma-deficient mice (IFN gamma(-/-)) were immunized with thymidine kinase-deficient HSV-2 (HSV-2 333tk(-)). HSV-specific cellular and humoral responses were elicited in immunized IFN gamma(-/-) mice resulting in increased resistance relative to non-immune C57BL/6J (B6) mice following challenge with fully virulent HSV-2. CD8(+) T cells from IFN gamma(-/-) mice displayed cytotoxic activity and secreted TNF alpha. HSV-specific CD4(+) T cells from immunized IFN gamma(-/-) mice secreted IL-4 TNF alpha, and IL-17, but unlike T cells from HSV-immune B6 mice, could not clear virus from genital tissue following adoptive transfer. HSV-immune IFN gamma(-/-) 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 naive 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 IFN gamma(-/-) mice to HSV-2 infection resulted from the action of HSV-specific Ab rather than IFN gamma-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 IFN gamma-induced IgG subclasses were more effective once virus had spread to neural tissues. (C) 2009 Elsevier Ireland Ltd. All rights reserved.