Cytomegalovirus-Specific IL-10-Producing CD4+ T Cells Are Governed by Type-I IFN-Induced IL-27 and Promote Virus Persistence

Autor: Clement, Mathew, Marsden, Morgan, Stacey, Maria A., Abdul-Karim, Juneid, Gimeno Brias, Silvia, Costa Bento, Diana, Scurr, Martin J., Ghazal, Peter, Weaver, Casey T., Carlesso, Gianluca, Clare, Simon, Jones, Simon A., Godkin, Andrew, Jones, Gareth W., Humphreys, Ian R.
Jazyk: angličtina
Rok vydání: 2016
Předmět:
CD4-Positive T-Lymphocytes
Interleukin-27
Physiology
Cytomegalovirus
Salivary Glands
White Blood Cells
Mice
Animal Cells
Immune Physiology
Medicine and Health Sciences
Biology (General)
Mice
Knockout
Innate Immune System
T Cells
Viral Persistence and Latency
Interleukin-10
QR180
Cytomegalovirus Infections
Interferon Type I
Cytokines
Cellular Types
Anatomy
Research Article
QH301-705.5
Immune Cells
Immunology
Cytotoxic T cells
Research and Analysis Methods
Microbiology
Exocrine Glands
Virology
Animals
Humans
Molecular Biology Techniques
Molecular Biology
QR355
Blood Cells
Biology and Life Sciences
Cell Biology
cytomegalovirus
CD4+ T-cells
IL-10
IL-27R
type-I IFN
Molecular Development
RC581-607
Viral Replication
Mice
Inbred C57BL
Disease Models
Animal
Immune System
Immunologic diseases. Allergy
Digestive System
Spleen
Cloning
Developmental Biology
Zdroj: PLoS Pathogens, Vol 12, Iss 12, p e1006050 (2016)
PLoS Pathogens
Clement, M, Marsden, M, Stacey, M A, Abdul-Karim, J, Gimeno Brias, S, Costa Bento, D, Scurr, M J, Ghazal, P, Weaver, C T, Carlesso, G, Clare, S, Jones, S A, Godkin, A, Jones, G W & Humphreys, I R 2016, ' Cytomegalovirus-Specific IL-10-Producing CD4+ T Cells Are Governed by Type-I IFN-Induced IL-27 and Promote Virus Persistence ', PLoS Pathogens, vol. 12, no. 12, pp. e1006050 . https://doi.org/10.1371/journal.ppat.1006050
Clement, M, Marsden, M, Stacey, M, Abdul-Karim, J, Brias, S G, Bento, D F C, Scurr, M, Weaver, C, Carlesso, G, Clare, S, Jones, S, Godkin, A, Ghazal, P, Jones, G W & Humphreys, I 2016, ' Cytomegalovirus-specific IL-10-producing CD4+ T cells are governed by type-I IFN-induced IL-27 and promote virus persistence ', PLoS Pathogens, vol. 12, no. 12, e1006050 . https://doi.org/10.1371/journal.ppat.1006050
ISSN: 1553-7374
1553-7366
DOI: 10.1371/journal.ppat.1006050
Popis: 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.
Author Summary Viruses including the pathogenic β-herpesvirus human cytomegalovirus (HCMV) can replicate within and disseminate from mucosal tissues. Understanding how to improve antiviral immune responses to restrict virus replication in the mucosa could help counter virus transmission. Studies in the murine cytomegalovirus (MCMV) model have demonstrated the importance of the CD4+ T cells in control of mucosal MCMV replication. However, this process is inefficient, allowing virus persistence. Herein, we reveal that production by CD4+ T cells of the immune-suppressive soluble protein, or cytokine, interleukin (IL)-10 facilitates virus persistence in mucosal tissue. Mice deficient in T cell-derived IL-10 mounted heightened T cell responses and reduced virus replication in the salivary glands and shedding in the saliva. The cytokine IL-27 induced IL-10-producing CD4+ T cells in the periphery whereas a cell surface-expressed protein, ICOS, promoted mucosal IL-10+ T cell responses. IL-27 acted in the initial stages of infection to impinge on T cell responses and antiviral control. In turn, IL-27 production in response to viral infection was triggered by type-I interferon, a prototypic antiviral cytokine. Thus, our data suggest that herpesviruses may exploit immune-suppressive properties of this early antiviral cytokine response to facilitate persistence within and shedding from mucosal tissue.
Databáze: OpenAIRE
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