Faculty Collaboration Database

Testing the role of P2X7 receptors in the development of type 1 diabetes in nonobese diabetic mice. J Immunol 2011 Apr 01;186(7):4278-84

Date

03/02/2011

Pubmed ID

21357538

Pubmed Central ID

PMC3094905

DOI

10.4049/jimmunol.1003733

Scopus ID

2-s2.0-79955013490 (requires institutional sign-in at Scopus site)   28 Citations

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.

Author List

Chen YG, Scheuplein F, Driver JP, Hewes AA, Reifsnyder PC, Leiter EH, Serreze DV

Author

Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

ADP-ribosyl Cyclase 1
Animals
CD4 Antigens
Cells, Cultured
Coculture Techniques
Diabetes Mellitus, Type 1
Female
Genetic Predisposition to Disease
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout
Natural Killer T-Cells
Receptors, Purinergic P2X7
T-Lymphocytes, Regulatory