Dysfunctional Mucosa-associated invariant T-cells link intestinal immunity with susceptibility to bacterial infection in Alcoholic Liver Disease
2017
Background/aims Intestinal permeability with systemic
distribution of bacterial products are central in the
immunopathogenesis of alcoholic liver disease (ALD), yet
links with intestinal immunity remain elusive. Mucosaassociated
invariant T cells (MAIT) are found in liver,
blood and intestinal mucosa and are a key component of
antibacterial host defences. Their role in ALD is unknown.
Methods/design We analysed frequency, phenotype,
transcriptional regulation and function of blood MAIT
cells in severe alcoholic hepatitis (SAH), alcohol-related
cirrhosis (ARC) and healthy controls (HC). We also
examined direct impact of ethanol, bacterial products
from faecal extracts and antigenic hyperstimulation
on MAIT cell functionality. Presence of MAIT cells in
colon and liver was assessed by quantitative PCR and
immunohistochemistry/gene expression respectively.
Results I n ARC and SAH, blood MAIT cells were
dramatically depleted, hyperactivated and displayed
defective antibacterial cytokine/cytotoxic responses.
These correlated with suppression of lineage-specific
transcription factors and hyperexpression of homing
receptors in the liver with intrahepatic preservation of
MAIT cells in ALD. These alterations were stronger in
SAH, where surrogate markers of bacterial infection
and microbial translocation were higher than ARC.
Ethanol exposure in vitro, in vivo alcohol withdrawal and
treatment with Escherichia coli had no effect on MAIT
cell frequencies, whereas exposure to faecal bacteria/
antigens induced functional impairments comparable
with blood MAIT cells from ALD and significant MAIT
cell depletion, which was not observed in other T cell
compartments.
Conclusions I n ALD, the antibacterial potency of MAIT
cells is compromised as a consequence of contact with
microbial products and microbiota, suggesting that the
’leaky’ gut observed in ALD drives MAIT cell dysfunction
and susceptibility to infection in these patients.
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