Human Cytomegalovirus Latency-Associated Proteins Elicit Immune-Suppressive IL-10 Producing CD4+ T Cells

• Published in: PLoS pathogens Vol. 9; no. 10; p. e1003635
• Main Authors: Mason, Gavin M., Jackson, Sarah, Okecha, Georgina, Poole, Emma, Sissons, J. G. Patrick, Sinclair, John, Wills, Mark R.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.10.2013; Public Library of Science (PLoS)
• Subjects: CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; Cytomegalovirus - physiology; Cytomegalovirus Infections - genetics; Cytomegalovirus Infections - immunology; Cytomegalovirus Infections - pathology; Female; Humans; Immune system; Immunology; Infections; Interferon-gamma - genetics; Interferon-gamma - immunology; Interleukin-10 - genetics; Interleukin-10 - immunology; Male; Microbiology; Receptors, Chemokine - genetics; Receptors, Chemokine - immunology; T cell receptors; Viral Proteins - genetics; Viral Proteins - immunology; Virus Latency - physiology
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1003635

Human cytomegalovirus (HCMV) is a widely prevalent human herpesvirus, which, after primary infection, persists in the host for life. In healthy individuals, the virus is well controlled by the HCMV-specific T cell response. A key feature of this persistence, in the face of a normally robust host immune response, is the establishment of viral latency. In contrast to lytic infection, which is characterised by extensive viral gene expression and virus production, long-term latency in cells of the myeloid lineage is characterised by highly restricted expression of viral genes, including UL138 and LUNA. Here we report that both UL138 and LUNA-specific T cells were detectable directly ex vivo in healthy HCMV seropositive subjects and that this response is principally CD4⁺ T cell mediated. These UL138-specific CD4⁺ T cells are able to mediate MHC class II restricted cytotoxicity and, importantly, show IFNγ effector function in the context of both lytic and latent infection. Furthermore, in contrast to CDCD4⁺ T cells specific to antigens expressed solely during lytic infection, both the UL138 and LUNA-specific CD4⁺ T cell responses included CD4⁺ T cells that secreted the immunosuppressive cytokine cIL-10. We also show that cIL-10 expressing CD4⁺ T-cells are directed against latently expressed US28 and UL111A. Taken together, our data show that latency-associated gene products of HCMV generate CD4⁺ T cell responses in vivo, which are able to elicit effector function in response to both lytic and latently infected cells. Importantly and in contrast to CD4⁺ T cell populations, which recognise antigens solely expressed during lytic infection, include a subset of cells that secrete the immunosuppressive cytokine cIL-10. This suggests that HCMV skews the T cell responses to latency-associated antigens to one that is overall suppressive in order to sustain latent carriage in vivo.