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.
2011. High levels of adenosine deaminase on dendritic cells promote autoreactive T cell activation and diabetes in nonobese diabetic mice. J. Immunol. 186: 6798-6806.There was a mistake in processing the FACS plots that resulted in a duplication of two panels. In Fig 4B, top row of the FACS plots, the right plot of the middle two plots (KO of Spleen) was incorrect. The revised Fig. 4 is published below. The legend for Fig. 4 was correct as published and is shown below for reference.www.jimmunol.org/cgi/doi/10.4049/jimmunol.1190043 FIGURE 4. Characterization of ADA-deficient NOD mice. A, D2.0 ADA KO alleles and the rescue minigene were bred into NOD mice for 10 generations. These mice were genotyped by PCR for the presence of the minigene and KO allele and the absence of the WT allele (1/8 probability). B, Cells from indicated sources from D2.0 NOD and NOD mice were stained for various immune markers. Overall, D2.0 NOD immune development was not drastically different from that of NOD. Pooled data from three or four independent experiments are presented in bar graphs to show the range. The lower right panel shows the small numbers of DCs. C, Similar to Fig. 2A, NOD or D2.0 NOD BMDCs were not treated or were stimulated with 5 mg/ml CpG, 5 ng/ ml LPS, or 0.0025% v/v killed E. coli. TNF-a production was measured after 24 h. LB, left bottom; LT, left top; RB, right bottom; RT, right top.
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