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,¶,**
,,**
* Department of Laboratory Medicine,
Department of Pediatrics,
Department of Microbiology, and
Program in Molecular and Cellular Biology, University of Washington, Seattle, WA, 98195;
¶ Infectious Disease and Immunology, Children’s Hospital and Regional Medical Center, Seattle, WA 98105;
|| Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL;
# Oregon Health and Science University, Portland, OR 97239; and
** Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
T lymphocytes are an essential component of the immune response against HSV infection. We previously reported that T cells became functionally impaired or inactivated after contacting HSV-infected fibroblasts. In our current study, we investigate the mechanisms of inactivation. We report that HSV-infected fibroblasts or HSV alone can inactivate T cells by profoundly inhibiting TCR signal transduction. Inactivation requires HSV penetration into T cells but not de novo transcription or translation. In HSV-inactivated T cells stimulated through the TCR, phosphorylation of Zap70 occurs normally. However, TCR signaling is inhibited at linker for activation of T cells (LAT) and at steps distal to LAT in the TCR signal cascade including inhibition of calcium flux and inhibition of multiple MAPK. Inactivation of T cells by HSV leads to the reduced phosphorylation of LAT at tyrosine residues critical for TCR signal propagation. Treatment of T cells with tyrosine phosphatase inhibitors attenuates inactivation by HSV, and stimulus with a mitogen that bypasses LAT phosphorylation overcomes inactivation. Our findings elucidate a potentially novel method of viral immune evasion that could be exploited to better manage HSV infection, aid in vaccine design, or allow targeted manipulation of T cell function.
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