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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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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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