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Gastroenterology. 2012 Jun;142(7):1516-25.e3. doi: 10.1053/j.gastro.2012.02.039. Epub 2012 Mar 16.

Binding of hepatitis A virus to its cellular receptor 1 inhibits T-regulatory cell functions in humans.

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  • 1Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA.

Abstract

BACKGROUND & AIMS:

CD4+ T-regulatory (Treg) cells suppress immune responses and control self-tolerance and immunity to pathogens, cancer, and alloantigens. Most pathogens activate Treg cells to minimize immune-mediated tissue damage and prevent clearance, which promotes chronic infections. However, hepatitis A virus (HAV) temporarily inhibits Treg-cell functions. We investigated whether the interaction of HAV with its cellular receptor 1 (HAVCR1), a T-cell co-stimulatory molecule, inhibits the function of Treg cells to control HAV infection.

METHODS:

We studied the effects of HAV interaction with HAVCR1 on human T cells using binding, signal transduction, apoptosis, activation, suppression, cytokine production, and confocal microscopy analyses. Cytokines were analyzed in sera from 14 patients with HAV infection using bead arrays.

RESULTS:

Human Treg cells constitutively express HAVCR1. Binding of HAV to HAVCR1 blocked phosphorylation of Akt, prevented activation of the T-cell receptor, and inhibited function of Treg cells. At the peak viremia, patients with acute HAV infection had no Treg-cell suppression function, produced low levels of transforming growth factor-β , which limited leukocyte recruitment and survival, and produced high levels of interleukin-22, which prevented liver damage.

CONCLUSIONS:

Interaction between HAV and its receptor HAVCR1 inhibits Treg-cell function, resulting in an immune imbalance that allows viral expansion with limited hepatocellular damage during early stages of infection-a characteristic of HAV pathogenesis. The mechanism by which HAV is cleared in the absence of Treg-cell function could be used as a model to develop anticancer therapies, modulate autoimmune and allergic responses, and prevent transplant rejection.

Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

PMID:
22430395
[PubMed - indexed for MEDLINE]
PMCID:
PMC3367104
Free PMC Article
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