MAIT cell activation in adolescents is impacted by bile acid concentrations and body weight

Abstract

Bile acids (BAs) are produced by liver hepatocytes and were recently shown to exert functions additional to their well-known role in lipid digestion. As yet it is not known whether the mucosal-associated invariant T (MAIT) cells, which represent 10-15% of the hepatic T cell population, are affected by BAs. The focus of the present investigation was on the association of BA serum concentration with MAIT cell function and inflammatory parameters as well as on the relationship of these parameters to body weight. Blood samples from 41 normal weight and 41 overweight children of the Lifestyle Immune System Allergy (LISA) study were analyzed with respect to MAIT cell surface and activation markers [CD107a, CD137, CD69, interferon (IFN)-γ, tumor necrosis factor (TNF)-α] after Escherichia coli stimulation, mRNA expression of promyelocytic leukemia zinc finger protein (PLZF) and major histocompatibility complex class I-related gene protein (MR1), the inflammatory markers C-reactive protein (CRP), interleukin (IL)-8 and macrophage inflammatory protein (MIP)-1α as well as the concentrations of 13 conjugated and unconjugated BAs. Higher body weight was associated with reduced MAIT cell activation and expression of natural killer cell marker (NKp80) and chemokine receptor (CXCR3). BA concentrations were positively associated with the inflammatory parameters CRP, IL-8 and MIP-1α, but were negatively associated with the number of activated MAIT cells and the MAIT cell transcription factor PLZF. These relationships were exclusively found with conjugated BAs. BA-mediated inhibition of MAIT cell activation was confirmed in vitro. Thus, conjugated BAs have the capacity to modulate the balance between pro-and anti-inflammatory immune responses.

Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti‐tumor immunity

“…Furthermore, BA‐mediated inhibition of MAIT cell activation in vitro was shown. Interestingly, overweight children in the LISA study had reduced MAIT activation 349 in agreement with obesity‐associated alterations in MAIT cell function and distribution in children and adults 350 . Recent studies indicate that MAIT cells display tumor promoting functions by suppressing T cells and NK cells in a murine model of melanoma lung metastasis 351 .…”

“…In children from the Lifestyle Immune System Allergy (LISA) cohort, Mendler and colleagues showed that BAs positively associated with pro‐inflammatory markers such as C‐reactive protein, IL‐8, and MIP‐1α. In contrast, a negative association between conjugated‐BA concentrations and the number of activated MAIT cells was found 349 . Furthermore, BA‐mediated inhibition of MAIT cell activation in vitro was shown.…”

“…In contrast, a negative association between conjugated-BA concentrations and the number of activated MAIT cells was found. 349 Furthermore, BA-mediated inhibition of MAIT cell activation in vitro was shown. Interestingly, overweight children in the LISA study had reduced MAIT activation 349 in agreement with obesity-associated alterations in MAIT cell function and distribution in children and adults.…”

MAIT Cells in Barrier Tissues: Lessons from Immediate Neighbors

“…A screen of secondary bile acids also found that LCA derivatives can reduce the T H 17:T reg balance in the intestinal lamina propria, by directly blocking RORgt-induced T H 17 differentiation and promoting T reg Foxp3 expression and differentiation in a mitochondrial ROS-dependent manner (168). MAIT cell activation and PLZF expression negatively correlate with serum concentrations of conjugated bile acids in teenage children, and in vitro bile acids inhibit MAIT cell activation in response to E. coli (169), so it would be important to explore whether intestinal bile acids promote homeostatic MAIT cell responses against commensals within a healthy functioning symbiotic intestinal environment.…”

Bile Acids: A Bridge Linking Gut Microbiota and NAFLD

“…Bile acids, however, have been reported to have regulatory effects on the function and activation of MAIT cells. A clinical study has revealed that BA concentrations, especially of conjugated BAs, are negatively associated with the number of activated MAIT cells [82]. In hepatocyte cell line L02, CA has been found to upregulate IL-7 expression by inducing FXR binding to the IL-7 promoter, which induces signal transduction and activation of transcription 5 (STAT5) phosphorylation in MAIT cells to increasingly produce inflammatory cytokines and granzyme B [83].…”