Characterization of mucosal-associated invariant T cells in alcoholic liver disease

Abstract

Alcoholic liver disease (ALD) is the one of major causes of mortality among hepatic diseases. Mucosal-associated invariant T (MAIT) cells are abundant in the human liver, composing up to 50% of T cells. In the aspects of ALD, both TCR-dependent and TCR-independent activations of MAIT cells are important because alcohol induce gut-leakage that causes influx of bacteria to liver and activated monocytes can secrete cytokines that can activate MAIT cells. Here, I identified that the frequencies and absolute cell numbers of blood MAIT cells were dramatically reduced in ALD patients, including patients with steatohepatitis (SH), steatofibrosis (SF) and advanced cirrhosis (AC), compared to healthy donors (HD). In addition, compared to donors with alcoholic without liver disease (AWLD), MAIT cells were depleted among liver-infiltrating lymphocytes in SH and SF patients, whereas that of AC group was recovered. However, pro-inflammatory cytokines such as IFN-γ, MIP-1β and IL-17A were increased in SH and SF patients by PMA/Ionomycin stimulation. Activation markers such as CD38 and HLA-DR and cytotoxic markers such as perforin and granzyme B in MAIT cells were significantly up-regulated in SF group. The concentration of IL-18 and D-Lactate was elevated in ALD patients and positively correlated with the frequency of activated MAIT cells. I found that in vitro hyper-stimulation of MAIT cells from healthy donors induced inflammatory activation and but also their apoptosis. Moreover, the results of RNA-seq showed that antigen-dependently or TCR-independently activated MAIT cells from HD had up-regulated inflammatory and apoptotic gene signatures compared to the control. The up-regulated or down-regulated gene sets from activated MAIT cells were significantly similar to those of sorted MAIT cells from ALD patients by gene set enrichment analysis. Furthermore, the activated MAIT cells had cytotoxicity to hepatocyte cell line, compared to non-activated MAIT cells. Taken together, our results suggest that increased IL-18 and D-Lactate in ALD patients would activate MAIT cells and induce apoptosis by hyper-activation. The distinct MAIT cells may be important in liver environments in the aspects of disease progression by damaging hepatocytes.