IL-10 distinguishes a unique population of activated, effector-like CD8+ T cells in murine acute liver inflammation

Abstract

Immune-mediated liver injury is a central feature of hyperinflammatory diseases, such as hemophagocytic syndromes, yet the immunologic mechanisms underlying those processes are incompletely understood. In this study, we used the toll-like receptor 9 (TLR9)-mediated model of a hemophagocytic syndrome known as macrophage activation syndrome (MAS) to dissect the predominant immune cell populations infiltrating the liver during inflammation. We identified CD8 T cells that unexpectedly produce interleukin-10 (IL-10) in addition to interferon-γ (IFN-γ) as a major hepatic population induced by TLR9 stimulation. Despite their ability to produce this anti-inflammatory cytokine, IL-10 hepatic CD8 T cells in TLR9-MAS mice did not resemble CD8 T suppressor cells. Instead, the induction of these cells occurred independently of antigen stimulation and was partially dependent on IFN-γ. IL-10 hepatic CD8 T cells demonstrated an activated phenotype and high turnover rate, consistent with an effector-like identity. Transcriptional analysis of this population confirmed a gene signature of effector CD8 T cells yet suggested responsiveness to liver injury-associated growth factors. Together, these findings suggest that IL-10 CD8 T cells induced by systemic inflammation to infiltrate the liver have initiated an inflammatory, rather than regulatory, program and may thus have a pathogenic role in severe, acute hepatitis.

Eosinophils Control Liver Damage by Modulating Immune Responses Against Fasciola hepatica

“…In agreement with our results, EPO or major basic protein-deficient mice infected with Litomosoides sigmodontis present increased levels of IL-10 in the thoracic cavity, and a decrease in IL-5, which were accompanied by increased numbers of worms in infected mice (59,60). Interestingly, IL-10 is associated with susceptibility of helminth infection (60) or with liver lesions caused by liver inflammation (61) or by helminth infection (62,63).…”

Lymphocyte-independent pathways underlie the pathogenesis of murine cytomegalovirus-associated secondary haemophagocytic lymphohistiocytosis

“…Correspondingly, augmented serum IL-10 is reported frequently in HLH patients [34][35][36][37], although disease may be associated with a marked reduction of T reg cells [24]. Therefore, rather than originating from T reg cells, the serum IL-10 present in HLH patients and mice probably emanates from macrophages, actively performing haemophagocytosis [42], or even from NK [41] or CD8 1 T cells [43].…”

“…However, flow cytometry did not reveal a pronounced drop in T reg cell percentage or absolute numbers, and T reg cell activation and proliferation markers were increased significantly post-infection, suggesting that T reg cells are not defective in MCMV-induced secondary HLH. Therefore, rather than originating from T reg cells, the serum IL-10 present in HLH patients and mice probably emanates from macrophages, actively performing haemophagocytosis [42], or even from NK [41] or CD8 1 T cells [43]. In addition to this inherent defect, primary HLH may result from an acquired T reg defect.…”

Immune regulation and cytotoxic T cell activation of IL-10 agonists – Preclinical and clinical experience

“…In viral liver infection and inflammation, TLR9 induces IL-10 producing CD8 + T cell. These IL-10 + CD8 + T cells, did not resemble a regulatory T cell population, but produced IFNγ and contributed to liver inflammation [60]. During coronavirus infection, cytolyticly active CD8 + T cells produce IL-10, which reduced CD8 + T cells bystander cell activation, resulting in decreased tissue damage [61].…”