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

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

doi:10.1371/journal.ppat.1006050

Cited by 46 publications

(110 citation statements)

References 75 publications

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“…For example, IL‐27 is required for the development of T‐bet + and C‐X‐C motif chemokine receptor 3 (CXCR3) + regulatory T cell (T reg ) populations following T helper type 1 (Th1)‐mediated inflammation using Toxoplasma gondii ‐challenged IL‐27R‐deficient mice . In this regard, the anti‐inflammatory properties of type I IFNs are attributed largely to the up‐regulation of IL‐27 and the subsequent promotion of IL‐10 . Consistent with these observations, prominent immunosuppressive roles were discovered for IL‐27 through investigations in mouse models of chronic infection and autoimmunity .…”

Section: The Inflammatory Significance Of Il‐6 and Il‐27mentioning

confidence: 76%

IL-27: a double agent in the IL-6 family

Jones

Hill

Cardús

et al. 2018

Clinical and Experimental Immunology

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Summary The cytokine interleukin (IL)‐6 is a major therapeutic target for the treatment of various inflammatory and autoimmune diseases. While IL‐6 receives considerable attention in studies of innate and adaptive immunity, the IL‐6‐related family member IL‐27 is recognized increasingly for its effects on cellular proliferation, differentiation and leucocyte effector functions. Both cytokines activate responses in myeloid and stromal tissue cells, where they direct the transition from innate to adaptive immunity. However, they are identified frequently as lymphokines that control responses in T cells and B cells. In this regard, IL‐27 often opposes the action of IL‐6. Here, we will review the role of IL‐6 and IL‐27 in inflammation, with a particular focus on inflammatory arthritis, and discuss their importance in the diagnosis, stratification and treatment of autoimmune disease.

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Section: The Inflammatory Significance Of Il‐6 and Il‐27mentioning

confidence: 76%

IL-27: a double agent in the IL-6 family

Jones

Hill

Cardús

et al. 2018

Clinical and Experimental Immunology

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“…Evidence from mouse models of MCMV infection have shown that production of cIL-10 can result in reduced viral clearance and a reduction in production of IFNγ by MCMV-specific T cells (49, 50). This could provide an explanation for the observation that, despite a functional immune response preventing overt HCMV mediated disease, older donors have detectable HCMV DNA in blood and urine (36, 37).…”

Section: Discussionmentioning

confidence: 99%

Latent Cytomegalovirus (CMV) Infection Does Not Detrimentally Alter T Cell Responses in the Healthy Old, But Increased Latent CMV Carriage Is Related to Expanded CMV-Specific T Cells

et al. 2017

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Human cytomegalovirus (HCMV) primary infection and periodic reactivation of latent virus is generally well controlled by T-cell responses in healthy people. In older donors, overt HCMV disease is not generally seen despite the association of HCMV infection with increased risk of mortality. However, increases in HCMV DNA in urine of older people suggest that, although the immune response retains functionality, immunomodulation of the immune response due to lifelong viral carriage may alter its efficacy. Viral transcription is limited during latency to a handful of viral genes and there is both an IFNγ and cellular IL-10 CD4+ T-cell response to HCMV latency-associated proteins. Production of cIL-10 by HCMV-specific CD4+ T-cells is a candidate for aging-related immunomodulation. To address whether long-term carriage of HCMV changes the balance of cIL-10 and IFNγ-secreting T-cell populations, we recruited a large donor cohort aged 23–78 years and correlated T-cell responses to 11 HCMV proteins with age, HCMV IgG levels, latent HCMV load in CD14+ monocytes, and T-cell numbers in the blood. IFNγ responses by CD4+ and CD8+ T-cells to all HCMV proteins were detected, with no age-related increase in this cohort. IL-10-secreting CD4+ T cell responses were predominant to latency-associated proteins but did not increase with age. Quantification of HCMV genomes in CD14+ monocytes, a known site of latent HCMV carriage, did not reveal any increase in viral genome copies in older donors. Importantly, there was a significant positive correlation between the latent viral genome copy number and the breadth and magnitude of the IFNγ T-cell response to HCMV proteins. This study suggests in healthy aged donors that HCMV-specific changes in the T cell compartment were not affected by age and were effective, as viremia was a very rare event. Evidence from studies of unwell aged has shown HCMV to be an important comorbidity factor, surveillance of latent HCMV load and low-level viremia in blood and body fluids, alongside typical immunological measures and assessment of the antiviral capacity of the HCMV-specific immune cell function would be informative in determining if antiviral treatment of HCMV replication in the old maybe beneficial.

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“…Indeed, at the height of the inflammatory response and once cellular immune responses are mounted, antiviral CD4 + and CD8 + T cells become the main sources of IL-10 ( Figure 1) [66][67][68][69][70][71][72]. Th1 cells can produce IL-10 [73] in response to intracellular protozoan [74,75], LCMV [72,76], MCMV [77][78][79], or influenza [68] infections among others. IL-10 production in Th1 cells is driven by TCR engagement but is not directly regulated by T-bet, the master transcription regulator of Th1 cell programming [80,81].…”

Section: Il-10 Production By Antiviral T Cellsmentioning

confidence: 99%

IL-10: A Multifunctional Cytokine in Viral Infections

Rojas

Avia

Martı́n

et al. 2017

Journal of Immunology Research

285

268

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The anti-inflammatory master regulator IL-10 is critical to protect the host from tissue damage during acute phases of immune responses. This regulatory mechanism, central to T cell homeostasis, can be hijacked by viruses to evade immunity. IL-10 can be produced by virtually all immune cells, and it can also modulate the function of these cells. Understanding the effects of this multifunctional cytokine is therefore a complex task. In the present review we discuss the factors driving IL-10 production and the cellular sources of the cytokine during antiviral immune responses. We particularly focus on the IL-10 regulatory mechanisms that impact antiviral immune responses and how viruses can use this central regulatory pathway to evade immunity and establish chronic/latent infections.

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

Cited by 46 publications

References 75 publications

IL-27: a double agent in the IL-6 family

IL-27: a double agent in the IL-6 family

Latent Cytomegalovirus (CMV) Infection Does Not Detrimentally Alter T Cell Responses in the Healthy Old, But Increased Latent CMV Carriage Is Related to Expanded CMV-Specific T Cells

IL-10: A Multifunctional Cytokine in Viral Infections

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