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Epstein-Barr virus IL-10 engages IL-10R1 by a two-step mechanism leading to altered signaling properties.

ABSTRACT: Human interleukin-10 (hIL-10) is a pleiotropic cytokine that is able to suppress or activate cellular immune responses to protect the host from invading pathogens. Epstein-Barr virus (EBV) encodes a viral IL-10 (ebvIL-10) in its genome that has retained the immunosuppressive activities of hIL-10 but lost the ability to induce immunostimulatory activities on some cells. These functional differences are at least partially due to the ?1000-fold difference in hIL-10 and ebvIL-10 binding affinity for the IL-10R1·IL-10R2 cell surface receptors. Despite weaker binding to IL-10R1, ebvIL-10 is more active than hIL-10 in inducing B-cell proliferation. To explore this counterintuitive observation further, a series of monomeric and dimeric ebvIL-10·hIL-10 chimeric proteins were produced and characterized for receptor binding and cellular proliferation on TF-1/hIL-10R1 cells that express high levels of the IL-10R1 chain. On this cell line, monomeric chimeras elicited cell proliferation in accordance with how tightly they bound to the IL-10R1 chain. In contrast, dimeric chimeras exhibiting the highest affinity for IL-10R1 exhibited reduced proliferative activity. These distinct activity profiles are correlated with kinetic analyses that reveal that the ebvIL-10 dimer is impaired in its ability to form a 1:2 ebvIL-10·IL-10R1 complex. As a result, the ebvIL-10 dimer functions like a monomer at low IL-10R1 levels, which prevents efficient signaling. At high IL-10R1 levels, the ebvIL-10 dimer is able to induce signaling responses greater than hIL-10. Thus, the ebvIL-10 dimer scaffold is essential to prevent activation of cells with low IL-10R1 levels but to maintain or enhance activity on cells with high IL-10R1 levels.

SUBMITTER: Yoon SI

PROVIDER: S-EPMC3410999 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Epstein-Barr virus IL-10 engages IL-10R1 by a two-step mechanism leading to altered signaling properties.

Yoon Sung Il SI Jones Brandi C BC Logsdon Naomi J NJ Harris Bethany D BD Kuruganti Srilalitha S Walter Mark R MR

The Journal of biological chemistry 20120612 32

Human interleukin-10 (hIL-10) is a pleiotropic cytokine that is able to suppress or activate cellular immune responses to protect the host from invading pathogens. Epstein-Barr virus (EBV) encodes a viral IL-10 (ebvIL-10) in its genome that has retained the immunosuppressive activities of hIL-10 but lost the ability to induce immunostimulatory activities on some cells. These functional differences are at least partially due to the ∼1000-fold difference in hIL-10 and ebvIL-10 binding affinity for ...[more]

PMID: 22692218

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Project description:Epstein-Barr virus (EBV) is convincingly associated with gastric cancer, nasopharyngeal carcinoma, and certain lymphomas, but its role in other cancer types remains controversial. To test the hypothesis that there are additional cancer types with high prevalence of EBV, we determined EBV viral expression in all the Cancer Genome Atlas Project (TCGA) mRNA sequencing (mRNA-seq) samples (n = 10,396) from 32 different tumor types. We found that EBV was present in gastric adenocarcinoma and lymphoma, as expected, and was also present in >5% of samples in 10 additional tumor types. For most samples, EBV transcript levels were low, which suggests that EBV was likely present due to infected infiltrating B cells. In order to determine if there was a difference in the B-cell populations, we assembled B-cell receptors for each sample and found B-cell receptor abundance (P ? 1.4 × 10-20) and diversity (P ? 8.3?×?10-27) were significantly higher in EBV-positive samples. Moreover, diversity was independent of B-cell abundance, suggesting that the presence of EBV was associated with an increased and altered B-cell population. IMPORTANCE Around 20% of human cancers are associated with viruses. Epstein-Barr virus (EBV) contributes to gastric cancer, nasopharyngeal carcinoma, and certain lymphomas, but its role in other cancer types remains controversial. We assessed the prevalence of EBV in RNA-seq from 32 tumor types in the Cancer Genome Atlas Project (TCGA) and found EBV to be present in >5% of samples in 12 tumor types. EBV infects epithelial cells and B cells and in B cells causes proliferation. We hypothesized that the low expression of EBV in most of the tumor types was due to infiltration of B cells into the tumor. The increase in B-cell abundance and diversity in subjects where EBV was detected in the tumors strengthens this hypothesis. Overall, we found that EBV was associated with an increased and altered immune response. This result is not evidence of causality, but a potential novel biomarker for tumor immune status.

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Dataset Information

Epstein-Barr virus IL-10 engages IL-10R1 by a two-step mechanism leading to altered signaling properties.

Publications

Epstein-Barr virus IL-10 engages IL-10R1 by a two-step mechanism leading to altered signaling properties.

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