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Stimulation of a subset of natural killer T cells by CD103⁺ DC is required for GM-CSF and protection from pneumococcal infection.

ABSTRACT: Innate-like T cells, including invariant natural killer T cells, mucosal-associated invariant T cells, and γδ T cells, are present in various barrier tissues, including the lung, where they carry out protective responses during infections. Here, we investigate their roles during pulmonary pneumococcal infection. Following infection, innate-like T cells rapidly increase in lung tissue, in part through recruitment, but T cell antigen receptor activation and cytokine production occur mostly in interleukin-17-producing NKT17 and γδ T cells. NKT17 cells are preferentially located within lung tissue prior to infection, as are CD103⁺ dendritic cells, which are important both for antigen presentation to NKT17 cells and γδ T cell activation. Whereas interleukin-17-producing γδ T cells are numerous, granulocyte-macrophage colony-stimulating factor is exclusive to NKT17 cells and is required for optimal protection. These studies demonstrate how particular cellular interactions and responses of functional subsets of innate-like T cells contribute to protection from pathogenic lung infection.

SUBMITTER: Murray MP

PROVIDER: S-EPMC8934033 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Stimulation of a subset of natural killer T cells by CD103<sup>+</sup> DC is required for GM-CSF and protection from pneumococcal infection.

Murray Mallory Paynich MP Crosby Catherine M CM Marcovecchio Paola P Hartmann Nadine N Chandra Shilpi S Zhao Meng M Khurana Archana A Zahner Sonja P SP Clausen Björn E BE Coleman Fadie T FT Mizgerd Joseph P JP Mikulski Zbigniew Z Kronenberg Mitchell M

Cell reports 20220101 2

Innate-like T cells, including invariant natural killer T cells, mucosal-associated invariant T cells, and γδ T cells, are present in various barrier tissues, including the lung, where they carry out protective responses during infections. Here, we investigate their roles during pulmonary pneumococcal infection. Following infection, innate-like T cells rapidly increase in lung tissue, in part through recruitment, but T cell antigen receptor activation and cytokine production occur mostly in inte ...[more]

PMID: 35021099

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Project description:Background & aimsChronic liver inflammation leads to fibrosis and cirrhosis and is associated with an accumulation of intrahepatic TNFα-secreting CD206+ macrophages, which may participate in maintaining chronic liver disease in a GM-CSF-dependent manner. We aimed to elucidate the exact role of GM-CSF in the development and progression of chronic liver disease.MethodsLiver immunohistochemistry and serum quantification were performed in patients with viral and non-viral-related liver disease to compare CD206+ monocyte/macrophages, fibrosis and GM-CSF. This was followed by functional validations in vitro and in vivo in humanised mice.ResultsUsing multiplex immunofluorescence and histo-cytometry, we show that highly fibrotic livers had a greater density of CD206+ macrophages that produced more TNFα and GM-CSF in the non-tumour liver regions of patients with hepatocellular carcinoma (n = 47), independent of aetiology. In addition, the absolute number of CD206+ macrophages strongly correlated with the absolute number of GM-CSF-producing macrophages. In non-HCC chronic HCV+ patients (n = 40), circulating GM-CSF levels were also increased in proportion to the degree of liver fibrosis and serum viral titres. We then demonstrated in vitro that monocytes converted to TNFα-producing CD206+ macrophage-like cells in response to bacterial products (lipopolysaccharide) in a GM-CSF-dependent manner, confirming the in vivo normalisation of serum GM-CSF concentration following oral antibiotic treatment observed in HBV-infected humanised mice. Finally, anti-GM-CSF neutralising antibody treatment reduced intrahepatic CD206+ macrophage accumulation and abolished liver fibrosis in HBV-infected humanised mice.ConclusionsWhile the direct involvement of CD206+ macrophages in liver fibrosis remains to be demonstrated, these findings show that GM-CSF may play a central role in liver fibrosis and could guide the development of anti-GM-CSF antibody-based therapy for the management of patients with chronic liver disease.Lay summaryLiver fibrosis is a major driver of liver disease progression. Herein, we have shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) plays an important role in the development of liver fibrosis. Our findings support the use of anti-GM-CSF neutralising antibodies for the management of patients with chronic liver disease resulting from both viral and non-viral causes.

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Stimulation of a subset of natural killer T cells by CD103⁺ DC is required for GM-CSF and protection from pneumococcal infection.

Publications

Stimulation of a subset of natural killer T cells by CD103<sup>+</sup> DC is required for GM-CSF and protection from pneumococcal infection.

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Dataset Information

Stimulation of a subset of natural killer T cells by CD103+ DC is required for GM-CSF and protection from pneumococcal infection.

Publications

Stimulation of a subset of natural killer T cells by CD103<sup>+</sup> DC is required for GM-CSF and protection from pneumococcal infection.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Stimulation of a subset of natural killer T cells by CD103⁺ DC is required for GM-CSF and protection from pneumococcal infection.