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Title 

Targeted disruption of CD38 accelerates autoimmune diabetes in NOD/Lt mice by enhancing autoimmunity in an ADP-ribosyltransferase 2-dependent fashion

Authors 

J ChenY G ChenP C ReifsnyderW H SchottChul Ho LeeM OsborneF ScheupleinF HaagF Koch-NolteD V SerrezeE H Leiter

Publisher 

American Association of Immunologists

Issue Date 

2006

Citation 

Journal of Immunology, vol. 176, no. 8, pp. 4590-4599

Keywords 

CD38 antigennicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferasenicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 2purine P2X7 receptorautoimmune diseaseCD4+ CD25+ T lymphocytediabetes mellitusgene disruptionmouseADP ribose transferases

Abstract 

Ubiquitously expressed CD38 and T cell-expressed ADP-ribosyltransferase 2 (ART2) are ectoenzymes competing for NAD substrate. CD38 exerts pleiotropic actions in hemopoietic and nonhemopoietic compartments via effects on calcium mobilization. ART2 is an ADP-ribosyltransferase on naive CD4+ and CD8+ T cells. ART2-catalyzed ADP-ribosylation of the P2X7 purinoreceptor elicits apoptosis. Transfer of a genetically disrupted CD38 allele into the autoimmune diabetes-prone NOD/Lt background accelerated diabetes onset in both sexes, whereas transfer of a disrupted ART2 complex had no effect. However, the fact that the accelerated pathogenesis mediated by CD38 deficiency required ART2 activity was demonstrated by combining both ART2 and CD38 deficiencies. Reciprocal bone marrow reconstitution studies demonstrated accelerated diabetes only when CD38-deficient bone marrow was transferred into CD38-deficient recipients. Neither decreases in β cell function nor viability were indicated. Rather, the balance between T-effectors and T-regulatory cells was disturbed in CD38-deficient but ART2-intact NOD mice. In these mice, significant reductions in total viable CD8+ T cells were observed. This was accompanied by an age-dependent increase in a diabetogenic CD8 clonotype. This in turn correlated with impaired T-regulatory development (10-fold reduction in Foxp3 mRNA expression). These changes were corrected when CD38 deficiency was combined with ART2 deficiency. Both ART2-deficient and CD38/ART2 combined deficient T cells were resistant to NAD-induced killing in vitro, whereas CD38-deficient but ART2-intact T cells showed increased sensitivity, particularly the CD4+CD25+ subset. Unexpectedly, diabetes development in the combined CD38/ART2 stock was strongly suppressed, possibly through epistatic interactions between genes linked to the targeted CD38 on Chromosome 5 and the ART2 complex on Chromosome 7.

URI 

https://doi.org/10.4049/jimmunol.176.8.4590

ISSN 

0022-1767

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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