Cytomegalovirus-specific IL-10-producing CD4+ T cells are governed by type-I IFN-induced IL-27 and promote virus persistence

Mathew Clement, Morgan Marsden, Maria Stacey, Juneid Abdul-Karim, Silvia Gimeno Brias, Diana Filipa Costa Bento, Martin Scurr, Casey Weaver, Gianluca Carlesso, Simon Clare, Simon Jones, Andrew Godkin, Peter Ghazal, Gareth W. Jones, Ian Humphreys

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

CD4+ T cells support host defence against herpesviruses and other viral pathogens. We identified that CD4+ T cells from systemic and mucosal tissues of hosts infected with the beta-herpesviridae human cytomegalovirus (HCMV) or murine cytomegalovirus (MCMV) express the regulatory cytokine interleukin (IL)-10. IL-10+CD4+ T cells co-expressed TH1-associated transcription factors and chemokine receptors. Mice lacking T cell-derived IL-10 elicited enhanced antiviral T cell responses and restricted MCMV persistence in salivary glands and secretion in saliva. Thus, IL-10+CD4+ T cells suppress antiviral immune responses against CMV. Expansion of this T-cell population in the periphery was promoted by IL-27 whereas mucosal IL-10+ T cell responses were ICOS-dependent. Infected Il27ralpha-deficient mice with reduced peripheral IL-10+CD4+ T cell accumulation displayed robust T cell responses and restricted MCMV persistence and shedding. Temporal inhibition experiments revealed that IL-27R signaling during initial infection was required for the suppression of T cell immunity and control of virus shedding during MCMV persistence. IL-27 production was promoted by type-I IFN, suggesting that beta-herpesviridae exploit the immune-regulatory properties of this antiviral pathway to establish chronicity. Further, our data reveal that cytokine signaling events during initial infection profoundly influence virus chronicity.
Original languageEnglish
Article numbere1006050
Number of pages26
JournalPLoS Pathogens
Volume12
Issue number12
Early online date7 Dec 2016
DOIs
Publication statusPublished - 7 Dec 2016

Keywords

  • cytomegalovirus, CD4+ T-cells, IL-10, IL-27R, type-I IFN

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