Macrophage and T Cell Produced IL-10 Promotes Viral Chronicity

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.

Regulator Versus Effector Paradigm: Interleukin-10 as Indicator of the Switching Response

“…The IL-10 is shown as crucial factor inhibiting the harmful effect of innate proinflammatory immune response only in a T helper (Th) 1-dominated milieu, but not if the balance is shifted toward a Th2 response [70]. Notably, studies on DCs have demonstrated that Th2 induction and modulation of migrating lymph DCs responses are controlled more strongly by the pathogen encountered than the DC subsets [58,65,73,74]. Similarly to DCs, effector CD8+ T cell response is inhibited during H5N1 viral infection by IL-10 producing CD8+ Treg cells [75,76].…”

“…Similarly to DCs, effector CD8+ T cell response is inhibited during H5N1 viral infection by IL-10 producing CD8+ Treg cells [75,76]. The induced manipulation toward the Th2 profile assures increased surviving possibility for different infective agents, such as viruses, chlamydias, and parasites [65, 67-69, 73,74,[77][78][79]. The early IL-10 production by T cell, B cell, and monocyte/macrophage (but not on NK and DC) activation can lead to chronicity of lymphocytic choriomeningitis and B hepatitis virus infections, and the IL-10-mediated early T cell Similarly to viral infections, parasite-induced IL-10 production by various immune cells is associated with impaired resistance to protozoan and nematodes [80,81,86,87].…”

IL-10 Controls Early Microglial Phenotypes and Disease Onset in ALS Caused by Misfolded Superoxide Dismutase 1

“…Furthermore, evidence suggests that IL-10 signaling, through its functional IL-10R1, exerts its antiinflammatory effects in part by selective induction/formation of the p50/p50 homodimers, known to suppress transcriptional NF-B activity (Driessler et al, 2004). Although in infections an overexpression of IL-10 may induce so-called immune escape and correlate with poor pathogen control (Nylén and Sacks, 2007;Couper et al, 2008;Bai et al, 2009;Richter et al, 2013), the immune-regulatory properties of IL-10 conferred protection in brain injuries including ischemia (Pérez-de Puig et al, 2013), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MTPT)-mediated striatal toxicity (Joniec-Maciejak et al, 2014), as well as in neurodegenerative disorders such as ALS. Our results clearly demonstrate that in SOD1-mutant-mediated ALS, experimental inhibition of IL-10 signaling markedly increases inflammatory markers in microglial cells and precipitates disease onset in SOD1 G93A mutant mice (Figs.…”

Exploitation of Interleukin-10 (IL-10) Signaling Pathways: Alternate Roles of Viral and Cellular IL-10 in Rhesus Cytomegalovirus Infection

“…Similarly, vaccination of mice with bacterially encoded glyceraldehyde phosphate dehydrogenase protein of group B streptococcus (74), the CyaA toxin of Bordetella pertussis (75), or the BopN virulence factor of Bordetella bronchiseptica (76), all of which have been identified as stimulators of expression of cIL-10, confers significant measures of protection against bacterial challenge. By extension, interruption of IL-10R1 signaling through antibodymediated blockade of cIL-10R1 significantly reduced virus production and in some cases cleared the infection from sites of persistence following MCMV or lymphocytic choriomeningitis virus infections (5,7,(77)(78)(79). Collectively, all of these studies open the possibility of targeting the IL-10R1 signaling pathway to prevent or treat ongoing pathogenic infections.…”