The RT6 (Art2) family of ADP-ribosyltransferases in rat and mouse

Viruses are believed to contribute to the pathogenesis of autoimmune type 1A diabetes in humans. This pathogenic process can be modeled in the BBDR rat, which develops pancreatic insulitis and type 1A-like diabetes after infection with Kilham’s rat virus (RV). The mechanism is unknown, but does not involve infection of the pancreatic islets. We first documented that RV infection of BBDR rats induces diabetes, whereas infection with its close homologue H-1 does not. Both viruses induced similar humoral and cellular immune responses in the host, but only RV also caused a decrease in splenic CD4+CD25+ T cells in both BBDR rats and normal WF rats. Surprisingly, RV infection increased CD4+CD25+ T cells in pancreatic lymph nodes of BBDR but not WF rats. This increase appeared to be due to the accumulation of nonproliferating CD4+CD25+ T cells. The results imply that the reduction in splenic CD4+CD25+ cells observed in RV-infected animals is virus specific, whereas the increase in pancreatic lymph node CD4+CD25+ cells is both virus and rat strain specific. The data suggest that RV but not H-1 infection alters T cell regulation in BBDR rats and permits the expression of autoimmune diabetes. More generally, the results suggest a mechanism that could link an underlying genetic predisposition to environmental perturbation and transform a “regulated predisposition” into autoimmune diabetes, namely, failure to maintain regulatory CD4+CD25+ T cell function.

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“…(ART2 is a rat surface alloantigen that marks a population of regulatory T cells (38).) Conversely, depletion of …”

Section: Cd62lmentioning

confidence: 99%

Infections That Induce Autoimmune Diabetes in BBDR Rats Modulate CD4+CD25+ T Cell Populations

Zipris

Hillebrands

Welsh

et al. 2003

The Journal of Immunology

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“…In the rat, there exist two ART2 alleles, previously known as T cell differentiation marker RT6. Interestingly, T cells expressing RT6 (ART2) were reported to induce resistance to autoimmune diabetes in diabetes-prone BB/W rats (5,6). In the mouse, two ART2 genes, ART2a and ART2b, have been described, besides ART1, ART3, ART4, and ART5, all of which may be expressed on lymphocytes, with exception of ART3 and ART5 (3,4,(7)(8)(9).…”

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confidence: 99%

Extracellular Nicotinamide Adenine Dinucleotide Induces T Cell Apoptosis In Vivo and In Vitro

Liu

Azhipa

Okamoto

et al. 2001

The Journal of Immunology

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Incubation of mouse T cells expressing the cell surface enzyme ADP ribosyltransferase with nicotinamide adenine dinucleotide (NAD) had been reported to cause ADP ribosylation of cell surface molecules, inhibition of transmembrane signaling, and suppression of immune responses. In this study, we analyze the reasons for these effects and report that contact of T cells with NAD causes cell death. Naive T cells when incubated with NAD and adoptively transferred into semiallogeneic mice fail to cause graft-vs-host disease, and when injected into syngeneic, T cell-deficient recipients do not reconstitute these mice. Rather, they accumulate in the liver, leading to an increase of apoptotic lymphocytes in this organ. Similar effects are induced by injection of NAD, shown to cause a dramatic increase of apoptotic CD3+, CD4+, and CD8+ cells in the liver. Consistent with this, in vitro incubation of naive T cells with NAD is shown to induce apoptosis. In contrast, no cell death is demonstrable when T cells are activated before incubation with NAD. It is concluded that ecto-NAD, as substrate of ADP ribosyltransferase, acts on naive, but not on activated CD69+ T cells.

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“…Diabetes-prone BB (DPBB) rats develop spontaneous hyperglycemia that is clearly autoimmune in origin (2,3). They are lymphopenic and severely deficient in cells that express the ART2 (formerly RT6) marker of regulatory T-cells (4). Coisogenic diabetes-resistant BB (BBDR) rats were developed from diabetes-prone forebears selected for normoglycemia.…”

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BB Rat Thymocytes Cultured in the Presence of Islets Lose Their Ability to Transfer Autoimmune Diabetes

et al. 2001

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Thymocytes from adult BB rats can adoptively transfer autoimmune diabetes to athymic recipients. It is also known that the development of BB rat T-cells is recapitulated in adult thymus organ cultures (ATOCs). Based on these observations, we tested the hypothesis that cells capable of the adoptive transfer of diabetes would be present in long-term ATOCs but could be rendered nondiabetogenic by co-culture with appropriate antigens. We observed that cells recovered from adult diabetes-resistant BB (BBDR) rat thymi cultured for up to 14 days can adoptively transfer disease to athymic WAG-rnu/rnu rats treated with polyinosinic: polycytidylic acid and a monoclonal antibody to preclude development of ART2a ؉ regulatory T-cells. Coculture of adult BBDR thymi in the presence of BBDR thyrocytes had no effect on the ability of recovered cells to induce diabetes in 70 -80% of adoptive recipients. In contrast, co-culture in the presence of islets prevented transfer of diabetes, on average, in >90% of recipients. Fresh islets, frozen islets, and islets pretreated with streptozotocin to deplete insulin were equally effective in preventing diabetes, but none prevented insulitis in nondiabetic recipients. Co-culture in the presence of islets was not associated with detectable alterations in phenotype or in the secretion of ␥-interferon or interleukin-4, either in cultures or in cells recovered from adoptive recipients. We conclude that islet antigens involved in the initiation of autoimmune diabetes in BB rats may be absent or deficient in BB rat thymi. T ype 1 diabetes is a heritable T-cell-mediated disorder characterized by insulitis, an inflammatory infiltration of pancreatic islets, and by the selective destruction of islet ␤-cells (1). BB rats are used extensively to model this disease. Diabetes-prone BB (DPBB) rats develop spontaneous hyperglycemia that is clearly autoimmune in origin (2,3). They are lymphopenic and severely deficient in cells that express the ART2 (formerly RT6) marker of regulatory T-cells (4). Coisogenic diabetes-resistant BB (BBDR) rats were developed from diabetes-prone forebears selected for normoglycemia. The immune system of BBDR rats is phenotypically normal (2,3). These animals never become diabetic spontaneously but readily develop insulitis, hyperglycemia, and lymphocytic thyroiditis when treated in vivo with an activator of the immune system and depleted of regulatory T-cells that express the ART2 maturational alloantigen (2,3).Both peripheral lymphoid cells (5) and thymocytes (6) from diabetes-resistant BBDR rats can adoptively transfer insulitis and thyroiditis to histocompatible athymic recipients. Successful transfer generally requires that recipients be treated with the nonspecific immune system activator polyinosinic:polycytidylic acid (poly I:C) and a monoclonal antibody to prevent the emergence of ART2 ϩ regulatory T-cells. These and other data suggest that intrathymic events permit the generation of autoreactive effector Tcells in BBDR rats (3).Attempts to modulate these intrathymic ...

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The RT6 (Art2) family of ADP-ribosyltransferases in rat and mouse

Cited by 20 publications

References 58 publications

Infections That Induce Autoimmune Diabetes in BBDR Rats Modulate CD4+CD25+ T Cell Populations

Infections That Induce Autoimmune Diabetes in BBDR Rats Modulate CD4+CD25+ T Cell Populations

Extracellular Nicotinamide Adenine Dinucleotide Induces T Cell Apoptosis In Vivo and In Vitro

BB Rat Thymocytes Cultured in the Presence of Islets Lose Their Ability to Transfer Autoimmune Diabetes

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