Journal article
GB virus C particles inhibit T cell activation via envelope E2 protein-mediated inhibition of TCR signaling
The Journal of immunology (1950), Vol.190(12), pp.6351-6359
06/15/2013
DOI: 10.4049/jimmunol.1300589
PMCID: PMC3965330
PMID: 23686495
Abstract
Viruses enter into complex interactions within human hosts, leading to facilitation or suppression of each other's replication. Upon coinfection, GB virus C (GBV-C) suppresses HIV-1 replication in vivo and in vitro, and GBV-C coinfection is associated with prolonged survival in HIV-infected people. GBV-C is a lymphotropic virus capable of persistent infection. GBV-C infection is associated with reduced T cell activation in HIV-infected humans, and immune activation is a critical component of HIV disease pathogenesis. We demonstrate that serum GBV-C particles inhibited activation of primary human T cells. T cell activation inhibition was mediated by the envelope glycoprotein E2, because expression of E2 inhibited TCR-mediated activation of Lck. The region on the E2 protein was characterized and revealed a highly conserved peptide motif sufficient to inhibit TCR-mediated signaling. The E2 region contained a predicted Lck substrate site, and substitution of an alanine or histidine for the tyrosine reversed TCR-signaling inhibition. GBV-C E2 protein and a synthetic peptide representing the inhibitory amino acid sequence were phosphorylated by Lck in vitro. The synthetic peptide also inhibited TCR-mediated activation of primary human CD4(+) and CD8(+) T cells. Extracellular microvesicles from GBV-C E2-expressing cells contained E2 protein and inhibited TCR signaling in bystander T cells not expressing E2. Thus, GBV-C reduced global T cell activation via competition between its envelope protein E2 and Lck following TCR engagement. This novel inhibitory mechanism of T cell activation may provide new approaches for HIV and immunoactivation therapy.
Details
- Title: Subtitle
- GB virus C particles inhibit T cell activation via envelope E2 protein-mediated inhibition of TCR signaling
- Creators
- Nirjal Bhattarai - Iowa City Veterans Affairs Medical Center, Iowa City, IA 52242, USAJames H McLindenJinhua XiangAlan L LandayErnest T ChiveroJack T Stapleton
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.190(12), pp.6351-6359
- DOI
- 10.4049/jimmunol.1300589
- PMID
- 23686495
- PMCID
- PMC3965330
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Grant note
- R01 AI-58740 / NIAID NIH HHS R01 AI058740 / NIAID NIH HHS
- Language
- English
- Date published
- 06/15/2013
- Academic Unit
- Microbiology and Immunology; Infectious Diseases; Internal Medicine
- Record Identifier
- 9984094349602771
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