Abstract
Human Cytomegalovirus (HCMV) is a widespread pathogen, infection with which can cause severe disease for immunocompromised individuals. The complex changes wrought on the host’s immune system during both productive and latent HCMV infection are well known. Infected cells are masked and manipulated and uninfected immune cells are also affected; peripheral blood mononuclear cell (PBMC) proliferation is reduced and cytokine profiles altered. Levels increase of the anti-inflammatory cytokine IL-10, which may be important for the establishment of HCMV infections and is required for the development of high viral titres by murine cytomegalovirus. The mechanisms by which HCMV affects T cell IL-10 secretion are not understood. We show here that treatment of PBMC with purified pUL11 induces IL-10 producing T cells as a result of pUL11 binding to the CD45 phosphatase on T cells. IL-10 production induced by HCMV infection is also in part mediated by pUL11. Supernatants from pUL11 treated cells have anti-inflammatory effects on untreated PBMC. Considering the mechanism, CD45 can be a positive or negative regulator of TCR signalling, depending on its expression level, and we show that pUL11 also has concentration dependent activating or inhibitory effects on T cell proliferation and on the kinase function of the CD45 substrate Lck. pUL11 is therefore the first example of a viral protein that can target CD45 to induce T cells with anti-inflammatory properties. It is also the first HCMV protein shown to induce T cell IL-10 secretion. Understanding the mechanisms by which pUL11-induced changes in signal strength influence T cell development and function may provide the basis for the development of novel antiviral treatments and therapies against immune pathologies.
Highlights
Human Cytomegalovirus (HCMV) is a ubiquitous human pathogen with a high seroprevalence of between 45 and 100% worldwide [1]
We identify a viral protein, pUL11, which can induce IL-10 expression by T cells and reduce the production of mediators of inflammation. pUL11 interacts with CD45, an immune system regulator that controls the sensitivity of T cells and has been linked to IL-10 production
We show that pUL11 can likewise affect T cell responses to stimuli, depending on its concentration, and suggest that this underlies its functions. pUL11 is the first viral protein known with this mechanism and further understanding of its effects may lead to the development of novel antiviral therapies and help in the treatment of immune system disorders
Summary
Human Cytomegalovirus (HCMV) is a ubiquitous human pathogen with a high seroprevalence of between 45 and 100% worldwide [1]. IL-10 inhibits the function of antigen presenting cells and the production of proinflammatory cytokines, resulting in impaired CD4 T cell responses [18,19] This has been suggested to contribute to the immunosuppressive effects seen during acute HCMV infection [8,9]. IL-10 producing T cells specific for both lytic and latent HCMV proteins have been identified in vivo, the mechanisms by which HCMV affects T cell IL-10 secretion during lytic infection are not yet understood in detail [25,26,27] It is, known that ligation of the lymphocyte phosphatase CD45 can induce T cell IL-10 production [28,29,30]. CD45 can act as both a positive and negative regulator of T cell receptor (TCR) signal strength, depending on its expression level, and we show that pUL11 can have both activating and inhibitory effects on T cell proliferation and on the kinase function of the CD45 substrate Lck
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