Mucosal-Associated Invariant T Cells Improve Nonalcoholic Fatty Liver Disease Through Regulating Macrophage Polarization

Abstract

Mucosal-associated invariant T (MAIT) cells, a novel population of innate-like lymphocytes, have been involved in various inflammatory and autoimmune diseases. However, their role in the development of nonalcoholic fatty liver disease (NAFLD) remains unclear. In this study, we investigated the alterations of phenotype and immunological function of MAIT cells in NAFLD. Analysis of PBMCs in 60 patients with NAFLD and 48 healthy controls (HC) revealed that circulating MAIT cell frequency decreased in NAFLD, especially in the patients with higher serum levels of γ-glutamyl transferase or total triglyceride. Functional alterations of circulating MAIT cells were also detected in NAFLD patients, such as the increased production of IL-4 whereas the decreased production of IFN-γ and TNF-α. Furthermore, elevated expression of CXCR6 was observed in circulating MAIT cells of patients. Meanwhile, we found an increased number of MAIT cells in the livers of NAFLD, and the number was even greater in patients with higher NAFLD activity score. Moreover, activated MAIT cells induced monocytes/macrophages differentiation into M2 phenotype in vitro. Additionally, MAIT cells were enriched and displayed Th2 type cytokines profile in livers of wild type mice fed with methionine and choline deficient diet (MCD). Notably, mice deficient of MAIT cells exhibited more severe hepatic steatosis and inflammation upon MCD, accompanied with more CD11c+ proinflammatory macrophages (M1) and less CD206+ anti-inflammatory macrophages (M2) in livers. Our results indicate that MAIT cells protect against inflammation in NAFLD through producing regulatory cytokines and inducing anti-inflammatory macrophage polarization, which may provide novel therapeutic strategies for NAFLD.

Mucosal-Associated Invariant T Cells Redistribute to the Peritoneal Cavity During Spontaneous Bacterial Peritonitis and Contribute to Peritoneal Inflammation

“…Stimulation with bacterial supernatants ex vivo confirmed previous studies on the dysfunctional nature of cMAIT cells as they responded with lower production of the proinflammatory cytokines TNF and IFN-g in response to bacterial stimulation, which is consistent with previous observations in chronic liver disease. 13,22 On the contrary, peritoneal cells from patients with advanced liver disease remained potent producers of IFN-g and TNF after stimulation with bacterial supernatants or phorbol myristate acetate/ionomycin. Having shown that MAIT cells differ in function and phenotype when compared with tissue resident MAIT cells 39 has important implications.…”

“…13 Performing and interpreting such studies is challenging because the cMAIT cell pool is depleted in patients with liver disease, and conflicting data exist whether MAIT cells accumulate in the diseased liver. 13,[21][22][23] Because the depleted cMAIT cell pool may differ from organ-resident MAIT cells, the aim of this study was to investigate the phenotype and function of human MAIT cells in the peritoneal cavity in decompensated cirrhosis and during the course of SBP.…”

Mucosal-associated invariant T cells and disease

“…In patients with nonalcoholic fatty liver disease (NAFLD), MAIT cells accumulate around fatty hepatocytes. Although mouse and human studies have demonstrated the profibrogenic properties of MAIT cells, Mr1 −/− mice fed a methionine-choline-deficient diet show enhanced steato sis, are more prone to liver injury and have more CD11c + M1-like inflammatory macrophages but fewer CD206 + M2-like macrophages 93 . Future studies will be needed to confirm this protective role of MAIT cells in a more relevant model of nonalcoholic steatohepatitis, and the contribution of IL-17 needs to be evaluated, as it is a major driver of NAFLD progression 132,133 .…”

“…The decreased frequency of blood MAIT cells in immunemediated diseases could also result from their death by apoptosis subsequent to sustained activation. Accordingly, in many autoimmune and inflammatory diseases, circulating MAIT cells express higher levels of activation and/or exhaustion markers, such as CD38, CD25, CD69 and PD-1 (reFs 16,18,69,70,73,83,85,87,89,93 ). Furthermore, in some diseases MAIT cell activation correlates with disease activity score (TaBle 3).…”

“…Indeed, alterations of MAIT cell responses in vitro suggest an exhausted status. After phorbol myristate acetate-ionomycin stimulation or upon MR1-dependent activation, MAIT cells from patients with autoimmune and immune-mediated diseases are usually less activated and produce fewer T helper 1 (T H 1)-type cytokines than MAIT cells from controls 16,18,73,77,78,82,83,[85][86][87]89,93 . In patients with SLE, MAIT cell exhaustion has been associated with dysfunction of the Ca 2+ -calcineurin-NFAT1 signalling pathway downstream of TCR stimulation 89 .…”