Testing the Role of P2X7 Receptors in the Development of Type 1 Diabetes in Nonobese Diabetic Mice

Abstract

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 P2X7 receptors. T1D development was not altered by P2X7 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 P2X7 receptors. Therefore, we asked whether T1D acceleration was suppressed in a double-KO NOD stock lacking both P2X7 and CD38 by rescuing CD4+ iNKT cells and Tregs from NAD-induced cell death. We demonstrated that P2X7 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 P2X7. T1D acceleration in CD38-deficient NOD mice also requires ART2 expression. If increased ADP ribosylation of P2X7 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 P2X7. 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/P2X7 double-KO line.