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Journal of Virology, November 2007, p. 12504-12514, Vol. 81, No. 22
0022-538X/07/$08.00+0     doi:10.1128/JVI.01111-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Herpes Simplex Virus Remodels T-Cell Receptor Signaling, Resulting in p38-Dependent Selective Synthesis of Interleukin-10{triangledown}

Derek D. Sloan1,2 and Keith R. Jerome1,2*

Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195,1 Vaccine and Infectious Diseases Institute, Fred Hutchinson Cancer Research Center, Seattle, Washington 981092

Received 22 May 2007/ Accepted 24 August 2007

Herpes simplex virus (HSV)-specific T cells are essential for viral clearance. However, T cells do not prevent HSV latent infection or reactivation, suggesting that HSV has the potential to modulate T-cell function. T-cell receptor (TCR) stimulation is a potent and specific means of activating T cells. To investigate how HSV affects T-cell function, we have analyzed how HSV affects TCR-stimulated intracellular signaling and cytokine synthesis in mock-infected and HSV-infected T cells. Mock-infected T cells stimulated through the TCR synthesized a broad range of cytokines that included the proinflammatory cytokines tumor necrosis factor alpha, gamma interferon, and interleukin-2. In contrast, HSV-infected T cells stimulated through the TCR selectively synthesized interleukin-10, a cytokine that suppresses cellular immunity and favors viral replication. To achieve selective interleukin-10 synthesis, HSV differentially affected TCR signaling pathways. HSV inhibited TCR-stimulated formation of the linker for activation of the T-cell signaling complex, and HSV inhibited TCR-stimulated NF-{kappa}B activation. At the same time, HSV activated the p38 and JNK mitogen-activated protein kinases as well as the downstream transcription factors ATF-2 and c-Jun. HSV did not inhibit TCR-stimulated activation of STAT3, a transcription factor involved in interleukin-10 synthesis. The activation of p38 was required for interleukin-10 synthesis in HSV-infected T cells. The ability of HSV to differentially target intracellular signaling pathways and transform an activating stimulus into an immunosuppressive response represents a novel strategy for pathogen-mediated immune modulation. Selective, TCR-stimulated interleukin-10 synthesis may play an important role in HSV pathogenesis.

* Corresponding author. Mailing address: 1100 Fairview Ave N., D3-345, Seattle, WA 98109. Phone: (206) 667-6793. Fax: (206) 667-4411. E-mail: kjerome{at}fhcrc.org

{triangledown} Published ahead of print on 5 September 2007.

Journal of Virology, November 2007, p. 12504-12514, Vol. 81, No. 22
0022-538X/07/$08.00+0     doi:10.1128/JVI.01111-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Aubert, M., Yoon, M., Sloan, D. D., Spear, P. G., Jerome, K. R. (2009). The Virological Synapse Facilitates Herpes Simplex Virus Entry into T Cells. J. Virol. 83: 6171-6183 [Abstract] [Full Text]  
  • Gillis, P. A., Okagaki, L. H., Rice, S. A. (2009). Herpes Simplex Virus Type 1 ICP27 Induces p38 Mitogen-Activated Protein Kinase Signaling and Apoptosis in HeLa Cells. J. Virol. 83: 1767-1777 [Abstract] [Full Text]  
  • Zahariadis, G., Wagner, M. J., Doepker, R. C., Maciejko, J. M., Crider, C. M., Jerome, K. R., Smiley, J. R. (2008). Cell-Type-Specific Tyrosine Phosphorylation of the Herpes Simplex Virus Tegument Protein VP11/12 Encoded by Gene UL46. J. Virol. 82: 6098-6108 [Abstract] [Full Text]  
  • Jerome, K. R. (2008). Viral Modulation of T-Cell Receptor Signaling. J. Virol. 82: 4194-4204 [Full Text]  


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