title: Inhibition of TCR signaling by herpes simplex virus.
abstract: 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.
authors.affiliation: Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Derek D
authors.initials: DD
authors.lastname: Sloan
authors.forename: Jin-Young
authors.initials: JY
authors.lastname: Han
authors.forename: Tracy K
authors.initials: TK
authors.lastname: Sandifer
authors.forename: Mary
authors.initials: M
authors.lastname: Stewart
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Hinz
authors.forename: Miri
authors.initials: M
authors.lastname: Yoon
authors.forename: David C
authors.initials: DC
authors.lastname: Johnson
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Spear
authors.forename: Keith R
authors.initials: KR
authors.lastname: Jerome
mesh_terms: D020013:Calcium Signaling / Q000502:physiology; D002461:Cell Line, Transformed; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology / Q000821:virology; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D018139:Simplexvirus / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D014759:Viral Envelope Proteins / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D016207:Cytokines; D006023:Glycoproteins; D011948:Receptors, Antigen, T-Cell; D018124:Receptors, Tumor Necrosis Factor; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus; C506028:TNFRSF14 protein, human; D014759:Viral Envelope Proteins; D015759:Ionomycin; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases