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NKT cells promote both type 1 and type 2 inflammatory responses in a mouse model of liver fibrosis.

ABSTRACT: Sterile liver inflammation and fibrosis are associated with many liver disorders of different etiologies. Both type 1 and type 2 inflammatory responses have been reported to contribute to liver pathology. However, the mechanisms controlling the balance between these responses are largely unknown. Natural killer T (NKT) cells can be activated to rapidly secrete cytokines and chemokines associated with both type 1 and type 2 inflammatory responses. As these proteins have been reported to accumulate in different types of sterile liver inflammation, we hypothesized that these cells may play a role in this pathological process. We have found that a transgenic NKT (tgNKT) cell population produced in the immunodeficient 2,4??NOD.Rag2^-/- mice, but not in 2,4??NOD.Rag2^+/- control mice, promoted a type 1 inflammatory response with engagement of the NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome. The induction of the type 1 inflammatory response was followed by an altered cytokine profile of the tgNKT cell population with a biased production of anti-inflammatory/profibrotic cytokines and development of liver fibrosis. These findings illustrate how the plasticity of NKT cells modulates the inflammatory response, suggesting a key role for the NKT cell population in the control of sterile liver inflammation.

SUBMITTER: Nilsson J

PROVIDER: S-EPMC7732838 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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NKT cells promote both type 1 and type 2 inflammatory responses in a mouse model of liver fibrosis.

Nilsson Julia J Hörnberg Maria M Schmidt-Christensen Anja A Linde Kajsa K Nilsson Maria M Carlus Marine M Erttmann Saskia F SF Mayans Sofia S Holmberg Dan D

Scientific reports 20201211 1

Sterile liver inflammation and fibrosis are associated with many liver disorders of different etiologies. Both type 1 and type 2 inflammatory responses have been reported to contribute to liver pathology. However, the mechanisms controlling the balance between these responses are largely unknown. Natural killer T (NKT) cells can be activated to rapidly secrete cytokines and chemokines associated with both type 1 and type 2 inflammatory responses. As these proteins have been reported to accumulat ...[more]

PMID: 33311540

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Project description:BACKGROUND & AIM:Natural killer T (NKT) cells are CD1d-restricted innate-like T cells that modulate innate and adaptive immune responses. Unlike the well-characterized invariant/type I NKT cells, type II NKT cells with a diverse T cell receptor repertoire are poorly understood. This study defines the pathogenic role of type II NKT cells in the etiology of chronic liver inflammation. METHODS:Transgenic mice with the Lck promoter directing CD1d overexpression on T cells in J?18 wild-type (Lck-CD1dTgJ?18+; type I NKT cell sufficient) and J?18-deficient (Lck-CD1dTgJ?18o, type I NKT cell deficient) mice were analyzed for liver pathology and crosstalk between type II NKT cells and conventional T cells. CD1d expression on T cells in peripheral blood samples and liver sections from autoimmune hepatitis patients and healthy individuals were also examined. RESULTS:Lck-CD1dTgJ?18o and Lck-CD1dTgJ?18+ mice developed similar degrees of liver pathology resembling chronic autoimmune hepatitis in humans. Increased CD1d expression on T cells promoted the activation of type II NKT cells and other T cells. This resulted in Th1-skewing and impaired Th2 cytokine production in type II NKT cells. Dysfunction of type II NKT cells was accompanied by conventional T cell activation and pro-inflammatory cytokine production, leading to a hepatic T/B lymphocyte infiltration, elevated autoantibodies and hepatic injury in Lck-CD1dTg mice. A similar mechanism could be extended to humans as CD1d expression is upregulated on activated human T cells and increased presence of CD1d-expressing T cells was observed in autoimmune hepatitis patients. CONCLUSIONS:Our data reveals enhanced crosstalk between type II NKT cells and conventional T cells, leading to a Th1-skewed inflammatory milieu, and consequently, to the development of chronic autoimmune liver disease. Lay summary: CD1d overexpression on T cells enhances crosstalk between type II NKT cells and T cells, resulting in their aberrant activation and leading to the development of chronic autoimmune liver disease.

Dataset Information

NKT cells promote both type 1 and type 2 inflammatory responses in a mouse model of liver fibrosis.

Publications

NKT cells promote both type 1 and type 2 inflammatory responses in a mouse model of liver fibrosis.

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