CTL Are Inactivated by Herpes Simplex Virus-Infected Cells Expressing a Viral Protein Kinase

Abstract

Numerous cell-to-cell signals tightly regulate CTL function. Human fibroblasts infected with HSV type 1 or 2 can generate such a signal and inactivate human CTL. Inactivated CTL lose their ability to release cytotoxic granules and synthesize cytokines when triggered through the TCR. Inactivation requires cell-to-cell contact between CTL and HSV-infected cells. However, inactivated CTL are not infected with HSV. The inactivation of CTL is sustainable, as CTL function remains impaired when the CTL are removed from the HSV-infected cells. IL-2 treatment does not alter inactivation, and the inactivated phenotype is not transferable between CTL, distinguishing this phenotype from traditional anergy and T regulatory cell models. CTL inactivated by HSV-infected cells are not apoptotic, and the inactivated state can be overcome by phorbol ester stimulation, suggesting that inactivated CTL are viable and that the signaling block is specific to the TCR. HSV-infected cells require the expression of US3, a viral protein kinase, to transmit the inactivating signal. Elucidation of the molecular nature of this signaling pathway may allow targeted manipulation of CTL function.

The Us3 Protein of Herpes Simplex Virus 1 Inhibits T Cell Signaling by Confining Linker for Activation of T Cells (LAT) Activation via TRAF6 Protein

“…Previous studies have suggest that T cells infection by HSV-1 occurs efficiently through cell-to-cell spread that relies on the virological synapse (24). Coincubation of T cells with HSV-infected fibroblast cells impairs cytokine production and cytotoxic T cell function (25)(26)(27)45). A proposed model suggests that Us3 in HSV-infected cells transmits an inhibitory signal to uninfected T cells, leading to T cell dysfunction (27).…”

“…Coincubation of T cells with HSV-infected fibroblast cells impairs cytokine production and cytotoxic T cell function (25)(26)(27)45). A proposed model suggests that Us3 in HSV-infected cells transmits an inhibitory signal to uninfected T cells, leading to T cell dysfunction (27). Nevertheless, Us3 has also been reported to prevent apoptosis A, B, and F).…”

“…In vitro infection of T cells by HSV appears to be facilitated by cell-to-cell spread (25,26). Furthermore, HSV entry is reported to attenuate T cell activation (27,28). However, it remains unsolved whether HSV-1 has a direct impact on the intracellular events in T cell activation.…”

Clearance of Herpes Simplex Virus Type 2 by CD8+T Cells Requires Gamma Interferon and either Perforin- or Fas-Mediated Cytolytic Mechanisms

“…The wild-type gene gave an amplified product of 293 bp, and the disrupted gene yielded a gene product of 6.4 kb in size. Screening for the disrupted IFN-␥ gene was performed as described by Sisto et al (48). Mice screening positive for both the OT-I transgene and the IFN-␥ or perforin knockout genotype were then bred back against IFN-␥ Ϫ/Ϫ or Pfp Ϫ/Ϫ knockout mice, respectively.…”

Herpes Simplex Virus Type 1 Latency-Associated Transcript Expression Protects Trigeminal Ganglion Neurons from Apoptosis

“…HSV can also evade the immune system by infecting and eliminating antiviral T cells (31). Infected tissue can also inactivate CD8 ϩ T cells through the expression of US3 (36).…”