Abstract
Liver fibrosis is the common response to chronic liver injury, and leads to cirrhosis and its complications. Persistent inflammation is a driving force of liver fibrosis progression. Mucosal-associated invariant T (MAIT) cells are non-conventional T cells that display altered functions during chronic inflammatory diseases. Here, we show that circulating MAIT cells are reduced in patients with alcoholic or non-alcoholic fatty liver disease-related cirrhosis while they accumulate in liver fibrotic septa. Using two models of chronic liver injury, we demonstrate that MAIT cell-enriched mice show increased liver fibrosis and accumulation of hepatic fibrogenic cells, whereas MAIT cell-deficient mice are resistant. Co-culture experiments indicate that MAIT cells enhance the proinflammatory properties of monocyte-derived macrophages, and promote mitogenic and proinflammatory functions of fibrogenic cells, via distinct mechanisms. Our results highlight the profibrogenic functions of MAIT cells and suggest that targeting MAIT cells may constitute an attractive antifibrogenic strategy during chronic liver injury.
Highlights
Liver fibrosis is the common response to chronic liver injury, and leads to cirrhosis and its complications
Advances in the understanding of liver fibrosis pathogenesis have underscored the critical sustained inflammation originating from resident and infiltrating immune cells, that drives the fibrogenic process during liver injury via direct effects on fibrogenic cell proinflammatory and profibrogenic functions, and contributes to its resolution[1,2,6]
We first evaluated the frequency of circulating T-cell subsets in the peripheral blood mononuclear cells (PBMC) from severe and less severe cirrhotic patients with alcoholic (ALD n = 63), and non-alcoholic fatty liver disease (NAFLD n = 11), and compared to that of healthy donors
Summary
Liver fibrosis is the common response to chronic liver injury, and leads to cirrhosis and its complications. Mucosal-associated invariant T (MAIT) cells are nonconventional T cells that express an evolutionarily conserved semi-invariant T cell antigen receptor (TCR) repertoire (made of an invariant Vα7.2-Jα33 in humans and Vα19-Jα33 in mice) and are restricted by the non-classical MHC-related molecule 1 (MR1)[8]. They are abundant in human blood, gut, and liver, and secrete cytokines such as IL-17, granzyme B (Gr-B), IFN-γ, and TNF. Our data unravel this non-conventional T-cell subset as a promising target for antifibrogenic therapy
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