Date Published: December 7, 2016
Publisher: Public Library of Science
Author(s): Mathew Clement, Morgan Marsden, Maria A. Stacey, Juneid Abdul-Karim, Silvia Gimeno Brias, Diana Costa Bento, Martin J. Scurr, Peter Ghazal, Casey T. Weaver, Gianluca Carlesso, Simon Clare, Simon A. Jones, Andrew Godkin, Gareth W. Jones, Ian R. Humphreys, Annette Oxenius.
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 β-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 Il27rα-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 β-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.
Human cytomegalovirus (HCMV) is a ubiquitous β-herpesvirus that establishes lifelong infection. Infectious virus is usually acquired by horizontal transmission via mucosal secretions and urine. HCMV infection is typically asymptomatic in healthy individuals. However in the immunocompromised such as HIV-infected individuals and patients receiving immune-suppressive drugs, the virus can reactivate with debilitating consequences [1,2]. Further, HCMV is the leading congenital infection in the World, infecting up to 2.5% of live births and causing life-long neurological defects .
Herein we reveal that cytokine responses induced upon acute MCMV infection influence antiviral T cell responses and virus replication during pathogen persistence. We identified that IL-27, which was produced by myeloid cells during the initial days of infection, promoted the generation of IL-10+CD4+ T cells in the spleen. Our data suggest that this IL-27-dependent induction of peripheral IL-10+CD4+ T cells was sufficient to impinge on T cell mediated control of virus chronicity in the mucosa. IL-27 production was dependent upon type-I IFN, implying that CMV exploits the immune-regulatory actions of this prototypic antiviral cytokine pathway to enable persistence and dissemination.