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P2X7 receptors regulate NKT cells in autoimmune hepatitis

Hiroki Kawamura1, Fred Aswad, Masahiro Minagawa

  • 1Departments of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, 90033, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|February 4, 2006
PubMed

Insights

Nicotinamide adenine dinucleotide (NAD) impacts natural killer T (NKT) cells via P2X7 receptors. NAD can protect against liver injury by inhibiting naive NKT cells but may worsen it by stimulating activated NKT cells.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Adenine nucleotides act as danger signals in T cells through purinergic receptors.
  • The role of adenine nucleotides in innate immunity, particularly in NKT cells, remained unclear.

Purpose of the Study:

  • To investigate the effects of nicotinamide adenine dinucleotide (NAD) on NKT cells and their role in immune responses.
  • To determine the mechanism by which NAD influences NKT cell activity and liver injury.

Main Methods:

  • In vitro assessment of NAD-induced annexin V staining in NKT cells.
  • In vivo studies using NAD treatment in mice to evaluate protection against Con A- and alpha-galactosylceramide-induced hepatitis.
  • Analysis of cytokine production in NKT cells from NAD-treated mice.
  • Studies involving P2X7 receptor knockout mice and ADP-ribosyltransferase deficient mice.

Main Results:

  • Micromolar NAD concentrations induced annexin V staining in NKT cells, dependent on P2X7 receptors.
  • NAD treatment protected mice from Con A- and alpha-galactosylceramide-induced hepatitis by decreasing NKT cell activity.
  • NAD exacerbated liver injury when administered to primed mice, by stimulating activated NKT cells via P2X7 receptors.
  • Mice lacking P2X7 receptors on lymphocytes or ADP-ribosyltransferase were resistant to Con A-induced hepatitis.

Conclusions:

  • Engagement of P2X7 receptors on NKT cells by NAD differentially regulates naive and activated cells.
  • NAD can suppress autoimmune hepatitis by inhibiting naive NKT cells but stimulate it by activating NKT cells.
  • P2X7 receptors and ADP-ribosyltransferase are key mediators in NAD's immunomodulatory effects on NKT cells and liver injury.

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