Introduction Intestinal bacterial translocation and systemic gut-derived bacterial products play a central role in the immunopathogenesis of alcoholic liver disease (ALD), yet the mechanisms of susceptibility to infection and the link with intestinal immunity remain elusive. Mucosal associated invariant T cells (MAIT) are unconventional T cells which only respond to bacteria-derived metabolites and are found in large numbers in the blood, intestinal mucosae and liver. They represent a key sentinel system for the homeostatic control of the gut flora and for the control of bacterial infections. The aim of this study was to assess the role of MAIT cells in ALD.
Method Peripheral blood mononuclear cells from subjects with acute alcoholic hepatitis (AAH, Maddrey’s discriminant function >32; n = 9), compensated alcohol-related cirrhosis (ARC, n = 9) and healthy controls (HC, n = 9) were examined by FACS. MAIT cells were identified as CD161+/Vα7.2+ CD8+T cells and MAIT-presenting cells (MPC) as MR1+ monocytes or B cells. We quantified (1) frequency, activation status (CD69/HLA-DR) and immunoinhibitory signatures (PD1/TIM3/LAG3) of MAIT cells; (2) frequency and immunoinhibitory status (PD1/PDL1/TIM3/mGal9) of MPC; (3) cytokine/cytotoxicity profiles (IFNγ/TNFα/IL17; GranzymeB (GrB)/Perforin/CD107a) of MAIT cells after in-vitro stimulation with fixed E. Coli. Plasma cytokines and endotoxin levels were assessed by ELISA.
Results MAIT frequencies were reduced in ARC (p = 0.005) and dramatically lower in AAH (p < 0.001) compared to HC. MAIT cells from AAH and ARC were activated and overexpressed immunoinhibitory receptors compared to HC (p < 0.03). Frequencies of MR1+ MPC were comparable in all groups but expression of immunoinhibitory molecules was higher in AAH and ARC (p < 0.03). Membrane-bound MPC Gal9 was lower in AAH and ARC (p < 0.01) than HC whereas soluble Gal9 was higher (p = 0.004). Levels of E. Coli-stimulated IFNγ from MAIT cells were comparable in all groups, but in ARC they produced less TNFα (p = 0.024) than HC. IL17 responses were observed only in HC. The cytotoxic potential of MAIT cells (GrB) was higher in AAH than HC.
Conclusion This is the first report addressing the role of MAIT cells in liver disease. We show that MAIT cells have quantitative and functional impairments in ALD, with defective TNFα and IL17 responses, increased killing potential and overexpression of immunoinhibitory receptors. MAIT cells may represent a novel immunotherapeutic target for ALD.
Disclosure of interest None Declared.