Levels of Art2⁺Cells but not Soluble Art2 Protein Correlate with Expression of Autoimmune Diabetes in the BB Rat

Abstract

ART2a and ART2b are isoenzymes expressed on the surface of mature T cells and intraepithelial lymphocytes (IELs) in the rat. They exhibit both adenosine diphosphoribosyltransferase and nicotine adenine dinucleotide (NAD) glycohydrolase activities, and both can generate a transmembrane signal that modulates T cell activation. The presence or absence of ART2+ T cells modulates the expression of autoimmune diabetes in the BB rat. ART2 also circulates in a soluble form whose function is unknown. We tested the hypothesis that circulating ART2 protein regulates the expression of autoimmunity. We compared the kinetics, regulation, and source of soluble ART2 in normal rats and in rats with autoimmune diabetes. Basal levels of soluble ART2 varied greatly among strains of rats and were lowest in the diabetes-prone BB (BBDP/Wor) rat. In diabetes-resistant BB (BBDR/Wor) rats, administration of anti-ART2a antibody, which is known to induce diabetes, resulted in transient clearing of soluble ART2a that was followed rapidly by a rebound increase. Repeated treatment of BBDR/Wor rats with anti-ART2a antibody resulted in sustained supraphysiologic levels of soluble ART2a. Although the number of peripheral ART2a+ T cells is known to correlate with the expression of diabetes in BBDR/Wor rats, the level of soluble ART2a protein did not. The source of the soluble ART2 protein in the rat appeared to be the gut. The results suggest that ART2+ T cells and soluble ART2 protein may subserve different immunomodulatory functions.

Deficiencies in Gut NK Cell Number and Function Precede Diabetes Onset in BB Rats

“…injections of DS4.23 anti-ART2.1 mAb (50 g five times weekly) plus poly(I:C) (5 g/100 g body weight three times weekly) as described (23,24); BBDR rats treated in this way uniformly develop autoimmune diabetes (23,24). Rats in the present study were treated for only 1 wk, less than the minimum time required for diabetes onset (25), and then killed for experimental analysis.…”

Experimental models of diabetes mellitus

“…The disorder is autoimmune, and insulitis is characterized by the infiltration of T lymphocytes, B lymphocytes, macrophages and NK cells (23). Typical for this species is extreme lymphopenia associated with a decreased number of T lymphocytes with an elevated expression of ADP-ribosyltransferase 2 (ART2); this has not been registered in the human population (24). A transfusion of histocompatible T ART2+ lymphocytes prevents spontaneous hyperglycemia in this model (24).…”

“…Typical for this species is extreme lymphopenia associated with a decreased number of T lymphocytes with an elevated expression of ADP-ribosyltransferase 2 (ART2); this has not been registered in the human population (24). A transfusion of histocompatible T ART2+ lymphocytes prevents spontaneous hyperglycemia in this model (24). Recent studies show that BB rat diabetic syndrome is a complex, polygenic disease that may share additional susceptibility genes aside from MHC class II with human type 1 diabetes (25).…”

NAD+-Consuming Enzymes in the Regulation of Lung Immune Responses

“…Recently it has been shown that T cell activation induces down modulation of P2X7 expression and shedding of ART2 by TACE metalloproteinase leading to resistance to NICD [4,7,38]. Alternatively, CD4+Foxp3+ regulatory cells were demonstrated to be highly sensitive to NICD through the ART2-P2X7 pathway [8,39]. This suggests that elimination of part of the naïve and regulatory T cells via ART2-dependent ADP-ribosylation would allow the expansion of Ag-primed T cell populations and thus increase T cell responses.…”

“…ART2 was shown as well to play an important role in autoimmune responses, since a deficiency of ART2 was observed in a model of autoimmune diabetes [39]. In the BB rat model of human type 1 diabetes, transfusion of ART2+ T cells protects the animals against autoreactive cells targeted to pancreatic beta cells [40].…”