Testing the role of P2X7 receptors in the development of type 1 diabetes in nonobese diabetic mice

J Immunol. 2011 Apr 1;186(7):4278-84. doi: 10.4049/jimmunol.1003733. Epub 2011 Feb 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-ribosyl Cyclase 1 / deficiency
  • ADP-ribosyl Cyclase 1 / genetics
  • ADP-ribosyl Cyclase 1 / physiology
  • Animals
  • CD4 Antigens / biosynthesis
  • Cells, Cultured
  • Coculture Techniques
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / metabolism*
  • Diabetes Mellitus, Type 1 / pathology
  • Female
  • Genetic Predisposition to Disease
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Natural Killer T-Cells / immunology
  • Natural Killer T-Cells / metabolism
  • Natural Killer T-Cells / pathology
  • Receptors, Purinergic P2X7 / deficiency
  • Receptors, Purinergic P2X7 / genetics
  • Receptors, Purinergic P2X7 / physiology*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • T-Lymphocytes, Regulatory / pathology

Substances

  • CD4 Antigens
  • P2rx7 protein, mouse
  • Receptors, Purinergic P2X7
  • ADP-ribosyl Cyclase 1