MAIT Cells Are Enriched and Highly Functional in Ascites of Patients With Decompensated Liver Cirrhosis

Abstract

List of abbreviationsARC, alcohol related cirrhosis; HXV, hepatitis virus related cirrhosis; IFNγ, interferon γ; MELD, model for end-stage liver disease; MNC, mononuclear cells; PBMC, peripheral blood mononuclear cells; SBP, spontaneous bacterial peritonitis; TCR, T cell receptor; TNF, tumor necrosis factor. Abstract Patients with advanced liver cirrhosis have an increased susceptibility to infections. As part of the cirrhosis-associated immune dysfunction, mucosal associated invariant T (MAIT) cells, that have the capacity to respond towards bacteria, are severely diminished in circulation and liver tissue. However, MAIT cell presence and function in the peritoneal cavity, a common anatomical site for infections in cirrhosis, remain elusive. To study this, matched peripheral blood and ascites fluid were collected from 35 patients with decompensated cirrhosis, with or without spontaneous bacterial peritonitis (SBP). MAIT cell phenotype and function were analyzed using highdimensional flow cytometry and obtained data was compared to blood samples of healthy controls (n=24) and patients with compensated cirrhosis (n=11). We found circulating MAIT cells to be severely decreased in cirrhotic patients as compared to controls. In contrast, in ascites fluid, MAIT cells were significantly increased together with CD14 + CD16 + monocytes, ILCs, and NK cells. This was paralleled by elevated levels of several pro-inflammatory cytokines and chemokines in ascites fluid as compared to plasma. Peritoneal MAIT cells displayed an activated tissue-resident phenotype and this was corroborated by increased functional responses following stimulation with E. coli or lL-12 + IL-18 as compared to circulating MAIT cells. During SBP, peritoneal MAIT cell frequencies increased most among all major immune cell subsets, suggestive of active homing of MAIT cells to the site of infection. Conclusions: Despite severely diminished MAIT cell numbers and impaired phenotype in circulation, peritoneal MAIT cells remain abundant, activated, and highly functional in decompensated cirrhosis and are further enriched in SBP. This suggests that peritoneal MAIT cells could be of interest for immune intervention strategies in patients with decompensated liver cirrhosis and SBP.

Mucosal‐Associated Invariant T Cell Dysregulation Correlates With Conjugated Bilirubin Level in Chronic HBV Infection

“…2F; Supporting Tables S2 and S3). In accord with reports that inflammation and fibrosis degree relates to change of MAIT cell frequency in liver disease settings, (26,27) we provide evidence to show the possible inflammatory cytokines contributing to reduced hepatic MAIT cell frequency.…”

Mucosal-associated invariant T cells in hepatitis B virus-related liver failure

“…The reason for this difference may include the number of patients and the different stages of the disease. In recent research, Niehaus et al[ 30 ] demonstrated enrichment of MAIT cells in the peritoneal cavity, but circulating MAIT cells were dramatically decreased in patients with cirrhosis. Also, they reported that MAIT cells in ascites were almost intact and highly activated.…”

Reversal of Immunity After Clearance of Chronic HCV Infection—All Reset?

“…In fact, of all alterations in peripheral blood immune cell subsets in chronic hepatitis C, loss of MAIT cells was shown to be the major phenotype ( 42 ). Loss of MAIT cells in chronic hepatitis C appears to both be a consequence of the infection, per se , but also to the underlying liver disease as patients with liver cirrhosis tend to have reduced numbers of MAIT cells ( 70 , 71 ). Loss of MAIT cells was accompanied with MAIT cell activation with increased expression of CD69, HLA-DR, PD-1, and granzyme B ( 42 ).…”

“…However, it is interesting to note that patients with chronic viral hepatitis infections progressing to end-stage liver disease have an increased risk for bacterial infections ( 72 ). This might partly be due to a dysfunctional MAIT cell compartment ( 71 ). Future research should focus on identifying the signals needed for restoring the MAIT cell compartment.…”