title: Binding of hepatitis A virus to its cellular receptor 1 inhibits T-regulatory cell functions in humans.
abstract: OBJECTIVE
  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.
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA.
authors.forename: Mohanraj
authors.initials: M
authors.lastname: Manangeeswaran
authors.forename: Jérôme
authors.initials: J
authors.lastname: Jacques
authors.forename: Cecilia
authors.initials: C
authors.lastname: Tami
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Konduru
authors.forename: Nadia
authors.initials: N
authors.lastname: Amharref
authors.forename: Oreste
authors.initials: O
authors.lastname: Perrella
authors.forename: Jose M
authors.initials: JM
authors.lastname: Casasnovas
authors.forename: Dale T
authors.initials: DT
authors.lastname: Umetsu
authors.forename: Rosemarie H
authors.initials: RH
authors.lastname: Dekruyff
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Alessandro
authors.initials: A
authors.lastname: Perrella
authors.forename: Gerardo G
authors.initials: GG
authors.lastname: Kaplan
mesh_terms: D002460:Cell Line; D006506:Hepatitis A / Q000276:immunology / Q000378:metabolism; D000072596:Hepatitis A Virus Cellular Receptor 1; D030041:Hepatitis A virus / Q000378:metabolism*; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011991:Receptors, Virus / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D053773:Transforming Growth Factor beta1 / Q000097:blood; D053585:Virus Attachment; D000097043:Interleukin-22
chemical_list: D000072596:Hepatitis A Virus Cellular Receptor 1; D007378:Interleukins; D008562:Membrane Glycoproteins; D051057:Proto-Oncogene Proteins c-akt; D011991:Receptors, Virus; D053773:Transforming Growth Factor beta1; D000097043:Interleukin-22; C491143:HAVCR1 protein, human; C494921:AKT2 protein, human