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Gastroenterology 2012 Jun;142(7):1516-25.e3

Binding of Hepatitis A Virus to its Cellular Receptor 1 Inhibits T-Regulatory Cell Functions in Humans.

Manangeeswaran M, Jacques J, Tami C, Konduru K, Amharref N, Perrella O, Casasnovas JM, Umetsu DT, Dekruyff RH, Freeman GJ, Perrella A, Kaplan GG


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- (TGF), which limited leukocyte recruitment and survival, and 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 infectiona 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 anti-cancer therapies, modulate autoimmune and allergic responses, and prevent transplant rejection.

Category: Journal Article
PubMed ID: #22430395 DOI: 10.1053/j.gastro.2012.02.039
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2012-03-22 Entry Last Modified: 2012-08-29