P2X7 receptors regulate NKT cells in autoimmune hepatitis.
Adenine nucleotides induce danger signals in T cells via purinergic receptors, raising the question whether they exert similar effects on innate immunity. Here we show that micromolar concentrations of nicotinamide adenine dinucleotide (NAD) induce a rapid increase of annexin V staining in NKT cells in vitro, a response that requires expression of P2X(7)Rs. Consistent with this result, treatment of mice with NAD causes a temporary decrease of NKT cells in the liver and protects from Con A- and alpha-galactosylceramide-induced hepatitis, both of which require functional NKT cells. Resistance to liver injury is associated with decreased cytokine production by NKT cells in NAD-treated mice. In contrast, when NAD is injected into Con A- or alpha-galactosylceramide-primed mice, liver injury is exacerbated and cytokine production by NKT cells is increased. This effect is caused by P2X(7)R-mediated stimulation of activated NKT cells. In agreement, mice lacking P2X(7)Rs on lymphocytes suffer reduced liver injury, and animals lacking ADP-ribosyltransferase, the enzyme that uses NAD to attach ADP-ribosyl groups to cell surfaces, are also resistant to Con A-induced hepatitis. These results prompt the conclusion that engagement of P2X(7)Rs on NKT cells inhibits naive, while stimulating activated cells, resulting in suppression or stimulation of autoimmune hepatitis.
Kawamura
Hiroki
H
Departments of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, 90033, USA.
Aswad
Fred
F
Minagawa
Masahiro
M
Govindarajan
Sugantha
S
Dennert
Gunther
G
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D019693:Hepatitis, Autoimmune / Q000276:immunology* / Q000378:metabolism* / Q000517:prevention & control; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D018942:Macrolides / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009243:NAD / Q000494:pharmacology; D018048:Receptors, Purinergic P2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*
D017304:Annexin A5; D016207:Cytokines; D018942:Macrolides; C546469:P2rx7 protein, mouse; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D009243:NAD; C036978:concanamycin A