High Levels of Adenosine Deaminase on Dendritic Cells Promote Autoreactive T Cell Activation and Diabetes in Nonobese Diabetic Mice

Abstract

Adenosine has been established as an important regulator of immune activation. It signals through P1 adenosine receptors to suppress activation of T cells and professional APCs. Adenosine deaminase (ADA) counters this effect by catabolizing adenosine. This regulatory mechanism has not been tested in a disease model in vivo. Questions also remain as to which cell types are most sensitive to this regulation and whether its dysregulation contributes to any autoimmune conditions. We approached this issue using the NOD model. We report that ADA is upregulated in NOD dendritic cells, which results in their exuberant and spontaneous activation. This, in turn, triggers autoimmune T cell activation. NOD DCs deficient in ADA expression have a greatly reduced capacity to trigger type I diabetes. We also provide evidence that although many cell types, particularly T cells, have been implicated as the suppression targets by adenosine in an in vitro setting, DCs also seem to be affected by this regulatory mechanism. Therefore, this report illustrates a role of ADA in autoimmunity and suggests a potential target for therapeutic intervention.

Regulation of Adenosine Deaminase on Induced Mouse Experimental Autoimmune Uveitis

“…Exogenous ADA was initially used to treat immune deficiencies involving ADA dysfunction (4; 9–11), but subsequent studies showed enhanced ADA function was associated with increased incidence of autoimmune disease (4; 12) and that suppression of aberrant ADA activity by ADA inhibitors has an anti-inflammatory effect (13; 14). Our interest in the use of ADA to treat autoimmune disease started with our early observation that ligands of adenosine A2A receptors (A2ARs) or adenosine A2B receptors (A2BRs) enhance, rather than suppress, Th17 autoreactive T cell responses (15–17).…”

The Immunosuppressive Role of Adenosine A2A Receptors in Ischemia Reperfusion Injury and Islet Transplantation

“…Interestingly, Satoh et al . also showed that successful islet transplantation from one donor to two recipients was feasible by targeting pro-inflammatory cytokines in mice: restoration of normogycemia was achieved in WT diabetic mice receiving 100 syngeneic islets graft by administration of anti-TNF-α and anti-IL-1β antibodies in conjunction with anti-IFN-γ antibody [169]. Transplantation of 200 syngeneic islets from a single donor pancreas into IFN-γ −/− mice produced similar results.…”

Adenosine signalling in diabetes mellitus—pathophysiology and therapeutic considerations

“…41 Data support the notion that adenosine and its receptors are involved in regulating the i nteractions between β cells and immune cells in T1DM. [42][43][44] Lymphocytes T lymphocytes are major targets of the immunoregulatory effects of adenosine. 11,45,46 Studies using A 2A adenosine receptor knockout mice suggest that activation of A 2A adenosine receptors inhibits IL-2 secretion by naive CD4 + T cells (activated by T-cell receptor stimulation) and reduces proliferation of these cells.…”

“…56 In vitro studies have highlighted the ability of adenosine to decrease the proinflammatory activity and increase the immune-suppressive functions of these cells. 44,57,58 Upregulation of adenosine deaminase expression in dendritic cells obtained from NOD mice is accompanied by robust and spontaneous activation of these cells, 42 which suggests that adenosine deaminase promotes dendritic-cell activation by removing the suppressive effect of adenosine and thus c ontributing to the onset of a utoimmune T cell dysregulation. 42 Despite our increasing awareness of the involvement of the adenosine system in orchestrating the activity of immune cells in T1DM, our understanding is far from Nature Reviews | Endocrinology …”