title: Testing the role of P2X7 receptors in the development of type 1 diabetes in nonobese diabetic mice.
abstract: Although P2rx7 has been proposed as a type 1 diabetes (T1D) susceptibility gene in NOD mice, its potential pathogenic role has not been directly determined. To test this possibility, we generated a new NOD stock deficient in P2X(7) receptors. T1D development was not altered by P2X(7) ablation. Previous studies found CD38 knockout (KO) NOD mice developed accelerated T1D partly because of a loss of CD4(+) invariant NKT (iNKT) cells and Foxp3(+) regulatory T cells (Tregs). These immunoregulatory T cell populations are highly sensitive to NAD-induced cell death activated by ADP ribosyltransferase-2 (ART2)-mediated ADP ribosylation of P2X(7) receptors. Therefore, we asked whether T1D acceleration was suppressed in a double-KO NOD stock lacking both P2X(7) and CD38 by rescuing CD4(+) iNKT cells and Tregs from NAD-induced cell death. We demonstrated that P2X(7) was required for T1D acceleration induced by CD38 deficiency. The CD38 KO-induced defects in homeostasis of CD4(+) iNKT cells and Tregs were corrected by coablation of P2X(7). T1D acceleration in CD38-deficient NOD mice also requires ART2 expression. If increased ADP ribosylation of P2X(7) in CD38-deficient NOD mice underlies disease acceleration, then a comparable T1D incidence should be induced by coablation of both CD38 and ART2, or CD38 and P2X(7). However, a previously established NOD stock deficient in both CD38 and ART2 expression is T1D resistant. This study demonstrated the presence of a T1D resistance gene closely linked to the ablated Cd38 allele in the previously reported NOD stock also lacking ART2, but not in the newly generated CD38/P2X(7) double-KO line.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Yi-Guang
authors.initials: YG
authors.lastname: Chen
authors.forename: Felix
authors.initials: F
authors.lastname: Scheuplein
authors.forename: John P
authors.initials: JP
authors.lastname: Driver
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Hewes
authors.forename: Peter C
authors.initials: PC
authors.lastname: Reifsnyder
authors.forename: Edward H
authors.initials: EH
authors.lastname: Leiter
authors.forename: David V
authors.initials: DV
authors.lastname: Serreze
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis; D002478:Cells, Cultured; D018920:Coculture Techniques; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D058486:Receptors, Purinergic P2X7 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D015704:CD4 Antigens; C546469:P2rx7 protein, mouse; D058486:Receptors, Purinergic P2X7; D051997:ADP-ribosyl Cyclase 1