Z Gastroenterol 2019; 57(01): e80
DOI: 10.1055/s-0038-1677261
5. Viral Hepatitis, Immunology
Georg Thieme Verlag KG Stuttgart · New York

Functional assessment of peritoneal mucosal associated invariant T (MAIT) cells in advanced cirrhosis

O Ibidapo-obe
1   Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital
,
S Stengel
1   Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital
,
N Köse
1   Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital
,
A Stallmach
1   Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital
,
M Bauer
2   Center for Sepsis Control and Care (CSCC), Jena University Hospital
3   Department of Anesthesiology and Intensive Care, Jena University Hospital, Jena
,
T Bruns
1   Department of Internal Medicine IV (Gastroenterology, Hepatology, and Infectious Diseases), Jena University Hospital
2   Center for Sepsis Control and Care (CSCC), Jena University Hospital
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

 

Background:

Mucosal associated invariant T (MAIT) cells are innate-like T cells that act as a bridge between the adaptive and innate arm of the immune system. They are fast-acting using their unique receptor (Vα7.2TCR) to recognize specific microbial riboflavin antigens presented on the MHC-Ib-related protein 1 (MR1) ligand of antigen presenting cells. Bacterial infections, including spontaneous bacterial peritonitis (SBP), are major complications of patients hospitalized for advanced liver cirrhosis leading to poor short-term prognosis due to impaired immune responses. In our previous experiments we had observed a depletion of MAIT cells in the peripheral blood from patients with cirrhosis and an accumulation in the peritoneal cavity during peritonitis.

Aims:

To investigate the effect of bacterial products on the function and migratory properties of MAIT cells in the peripheral blood and peritoneal cavity during complications of cirrhosis.

Methods:

Mononuclear cells obtained from peripheral blood and ascitic fluid from patients with decompensated cirrhosis and healthy controls were used for in vitro cell culture studies. Cells were cultured with filtered bacterial supernatants from vitamin B2+ and vitamin B2- bacteria to assess activation status and cytokine production. In some experiments, antigen-presenting cells were treated with anti-MR1 blocking antibody before stimulation. Baseline expression of MR1 on monocytes and peritoneal macrophages was assessed. The migratory properties of activated MAIT cells was investigated using transwell-insert migration technique. Results were analyzed using flow cytometry.

Results:

Circulating and peritoneal MAIT cells from patients with cirrhosis expressed higher levels of surface CD69 compared to circulating MAIT cells from healthy controls indicating recent activation. Filtered ascitic fluid from patients with SBP was sufficient to activate MAIT cells from healthy individuals. Treatment with cell-free bacterial supernatants from E. coli insufficiently activated circulating MAIT cells from patients with decompensated cirrhosis compared to healthy controls and resulted in reduced production of TNF-α and IFN-γ. In contrast to circulating MAIT cells, peritoneal MAIT cells from patients with cirrhosis did not show such an exhausted phenotype but responded sufficiently toward stimulation with bacterial products. Although MR-1 expression was higher on peritoneal macrophages as compared to circulating monocytes, this activation of peritoneal MAIT cells was independent of MR-1 as shown by blocking experiments.

Using in vitro migration assays, we could observe a preferential migration of activated MAIT cells towards filtered ascitic fluid from patients with SBP in comparison patients without SBP. Consistent with their chemokine receptor expression profiles (CCR6, CCR5, CXCR3), we observed preferential migration of activated MAIT cells towards CCL5, CXCL10 and CCL20 as compared to conventional T cells. Peritoneal MAIT cell expression of CD69 correlated with the severity of liver disease in the absence of SBP, and with markers of inflammation in the presence of SBP.

Conclusion:

Our results suggest that MAIT cells are preferentially recruited over conventional T cells to the peritoneal cavity in the context of SBP. In contrast to circulating MAIT cells, which are dysfunctional in decompensated cirrhosis, peritoneal MAIT cells remain potent producers of inflammatory cytokines and their activation status correlates with more severe liver disease.