Differential IL-21 signaling in APCs leads to disparate Th17 differentiation in diabetes-susceptible NOD and diabetes-resistant NOD.Idd3 mice
Sue M. Liu, David H. Lee, Jenna M. Sullivan, Denise Chung, Anneli Jäger, Bennett O.V. Shum, Nora E. Sarvetnick, Ana C. Anderson, Vijay K. Kuchroo
Sue M. Liu, David H. Lee, Jenna M. Sullivan, Denise Chung, Anneli Jäger, Bennett O.V. Shum, Nora E. Sarvetnick, Ana C. Anderson, Vijay K. Kuchroo
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Research Article Autoimmunity

Differential IL-21 signaling in APCs leads to disparate Th17 differentiation in diabetes-susceptible NOD and diabetes-resistant NOD.Idd3 mice

Abstract

Type 1 diabetes (T1D) is an autoimmune disease that shows familial aggregation in humans and likely has genetic determinants. Disease linkage studies have revealed many susceptibility loci for T1D in mice and humans. The mouse T1D susceptibility locus insulin-dependent diabetes susceptibility 3 (Idd3), which has a homologous genetic interval in humans, encodes cytokine genes Il2 and Il21 and regulates diabetes and other autoimmune diseases; however, the cellular and molecular mechanisms of this regulation are still being elucidated. Here we show that T cells from NOD mice produce more Il21 and less Il2 and exhibit enhanced Th17 cell generation compared with T cells from NOD.Idd3 congenic mice, which carry the protective Idd3 allele from a diabetes-resistant mouse strain. Further, APCs from NOD and NOD.Idd3 mice played a central role in this differential Th17 cell development, and IL-21 signaling in APCs was pivotal to this process. Specifically, NOD-derived APCs showed increased production of pro-Th17 mediators and dysregulation of the retinoic acid (RA) signaling pathway compared with APCs from NOD.Idd3 and NOD.Il21r-deficient mice. These data suggest that the protective effect of the Idd3 locus is due, in part, to differential RA signaling in APCs and that IL-21 likely plays a role in this process. Thus, we believe APCs provide a new candidate for therapeutic intervention in autoimmune diseases.

Authors

Sue M. Liu, David H. Lee, Jenna M. Sullivan, Denise Chung, Anneli Jäger, Bennett O.V. Shum, Nora E. Sarvetnick, Ana C. Anderson, Vijay K. Kuchroo

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Figure 5

Gene profiling of cells from NOD and NOD.Idd3 mice.

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Gene profiling of cells from NOD and NOD.Idd3 mice. RNA was extracte...
RNA was extracted from purified CD11b+ cells cultured for 4 hours with or without PGN. (A) Scatter plot shows gene profiling performed on duplicate CD11b+ cell samples from NOD and NOD.Idd3 mice cultured with or without PGN stimulation for 4 hours. Red dots indicate transcripts downstream of RA signaling. (B) The biological network showing differentially regulated genes in the RA pathway was produced with Ingenuity Pathways Analysis software. Genes expressed differentially more than 2 fold in CD11b+ cells from NOD and NOD.Idd3 mice are shaded pink, whereas more highly expressed genes are depicted by a darker pink and red. Indirect (dashed lines) and direct (solid lines) network interactions are shown. The asterisk denotes that this gene has multiple identifiers on the genechip. (C and D) Expression of RA-regulated genes was determined by real-time PCR and normalized to β-actin expression.