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

Johnson, Alison J.; Nelson, Michelle H.; Bird, Melanie D.; Chu, Chin-Fun; Milligan, Gregg N.

doi:10.1016/j.jri.2009.09.007

« Previous Next »Journal of Reproductive Immunology
Volume 84, Issue 1 , Pages 8-15, January 2010

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

Alison J. Johnson
- Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
Michelle H. Nelson
- Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
Melanie D. Bird
- Department of Pathology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
- Present address: Department of Surgery, Burn Shock Trauma Institute, Loyola Medical Center, Maywood, IL 60153, USA.
Chin-Fun Chu
- Department of Pediatrics, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
Gregg N. Milligan
- Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
- Department of Pediatrics, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
- Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
- Corresponding author at: Department of Pediatrics, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0436, USA. Tel.: +1 409 747 8145; fax: +1 409 747 8150.

Received 16 July 2009; received in revised form 3 September 2009; accepted 16 September 2009. published online 18 November 2009.

Abstract

Interferon gamma (IFNγ) is important for immune resistance to herpes simplex virus (HSV) infection. To examine the influence of IFNγ on the development of HSV-specific immune responses and test for IFNγ-independent adaptive immune mechanisms of protection, IFNγ-deficient mice (IFNγ^−/−) were immunized with thymidine kinase-deficient HSV-2 (HSV-2 333tk⁻). HSV-specific cellular and humoral responses were elicited in immunized IFNγ^−/− mice resulting in increased resistance relative to non-immune C57BL/6J (B6) mice following challenge with fully virulent HSV-2. CD8⁺ T cells from IFNγ^−/− mice displayed cytotoxic activity and secreted TNFα. HSV-specific CD4⁺ T cells from immunized IFNγ^−/− mice secreted IL-4, TNFα, and IL-17, but unlike T cells from HSV-immune B6 mice, could not clear virus from genital tissue following adoptive transfer. HSV-immune IFNγ^−/− mice produced predominantly IgG₁ 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 IFNγ^−/− mice to HSV-2 infection resulted from the action of HSV-specific Ab rather than IFNγ-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 IFNγ-induced IgG subclasses were more effective once virus had spread to neural tissues.