Abstract
Chronic viral infections lead to CD8+ T cell exhaustion, characterized by impaired cytokine secretion. Presence of the immune-regulatory cytokine IL-10 promotes chronicity of Lymphocytic Choriomeningitis Virus (LCMV) Clone 13 infection, while absence of IL-10/IL-10R signaling early during infection results in viral clearance and higher percentages and numbers of antiviral, cytokine producing T cells. IL-10 is produced by several cell types during LCMV infection but it is currently unclear which cellular sources are responsible for induction of viral chronicity. Here, we demonstrate that although dendritic cells produce IL-10 and overall IL-10 mRNA levels decrease significantly in absence of CD11c+ cells, absence of IL-10 produced by CD11c+ cells failed to improve the LCMV-specific T cell response and control of LCMV infection. Similarly, NK cell specific IL-10 deficiency had no positive impact on the LCMV-specific T cell response or viral control, even though high percentages of NK cells produced IL-10 at early time points after infection. Interestingly, we found markedly improved T cell responses and clearance of normally chronic LCMV Clone 13 infection when either myeloid cells or T cells lacked IL-10 production and mice depleted of monocytes/macrophages or CD4+ T cells exhibited reduced overall levels of IL-10 mRNA. These data suggest that the decision whether LCMV infection becomes chronic or can be cleared critically depends on early CD4+ T cell and monocyte/macrophage produced IL-10.
Highlights
The functional down regulation of antiviral T cells, termed T cell exhaustion, is a major hurdle inhibiting the control or even clearance of chronic infections
Chronic viral infections like Hepatitis B and C Virus (HBV and HCV) and Human Immunodeficiency Virus (HIV) in humans affect more than 500 million people worldwide
IL-10 is produced by several cell types during chronic Lymphocytic Choriomeningitis Virus (LCMV) infection but it is currently unclear which cellular sources are responsible to promote viral chronicity
Summary
The functional down regulation of antiviral T cells, termed T cell exhaustion, is a major hurdle inhibiting the control or even clearance of chronic infections. The host-derived anti-inflammatory cytokine IL-10 is an important player in driving T cell exhaustion and viral chronicity in LCMV Clone 13 infected mice [2,3], a commonly used murine model for chronic viral infections. Since disruption of IL-10 receptor signaling enhances CD8+ T cell effector functions after LCMV infection [2,3], and in case of HIV-, HBV- or HCV-specific T cells [6,7,8,9], interference with IL-10 signaling is currently proposed as a target for immune-based interventions during chronic viral infections. IL-10 is expressed during several persistent infections It may on the one hand favor viral chronicity by suppressing the antiviral immune response, but on the other hand protect the host from immunopathology [10,11]. Rhesus macaques infected with rhesus CMV deficient for rhcmvIL-10 exhibit a T and B cell response of higher quality and quantity [13]
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