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

PLoS Pathogens

Georgina Okecha¹  Emma Poole¹  Mark R. Wills¹  J. G. Patrick Sissons¹  John Sinclair¹  Gavin M. Mason¹  Sarah Jackson¹ 

[1] University of Cambridge, Department of Medicine, Cambridge, Cambridgeshire, United Kingdom

关键词: T cells;    Cytokines;    Monocytes;    Enzyme-linked immunoassays;    Immune response;    Cytotoxic T cells;    Human cytomegalovirus;    Regulatory T cells;   

DOI  :  10.1371/journal.ppat.1003635

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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 CD4+ 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.

【 授权许可】

CC BY