Macrophage IFN-I signaling promotes autoreactive T cell infiltration into islets in type 1 diabetes model
Brett S. Marro, Sarah Legrain, Brian C. Ware, Michael B.A. Oldstone
Brett S. Marro, Sarah Legrain, Brian C. Ware, Michael B.A. Oldstone
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Research Article Immunology

Macrophage IFN-I signaling promotes autoreactive T cell infiltration into islets in type 1 diabetes model

Abstract

Here, we report a pathogenic role for type I IFN (IFN-I) signaling in macrophages, and not β cells in the islets, for the development of type 1 diabetes (T1D). Following lymphocytic choriomeningitis (LCMV) infection in the Rip-LCMV-GP T1D model, macrophages accumulated near islets and in close contact to islet-infiltrating GP-specific (autoimmune) CD8+ T cells. Depletion of macrophages with clodronate liposomes or genetic ablation of Ifnar in macrophages aborted T1D, despite proliferation of GP-specific (autoimmune) CD8+ T cells. Histopathologically, disrupted IFNα/β receptor (IFNAR) signaling in macrophages resulted in restriction of CD8+ T cells entering into the islets with significant lymphoid accumulation around the islet. Collectively, these results provide evidence that macrophages via IFN-I signaling, while not entering the islets, are directly involved in interacting, directing, or restricting trafficking of autoreactive-specific T cells into the islets as an important component in causing T1D.

Authors

Brett S. Marro, Sarah Legrain, Brian C. Ware, Michael B.A. Oldstone

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Figure 1

Expression of IFNAR in insulin-producing β cells has a minor role in the development of T1D.

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Expression of IFNAR in insulin-producing β cells has a minor role in the...
(A) qPCR analysis of IFNα, Mx1, Ifit1, Ifit2, Stat1, and Oasl2 mRNA expression in pancreatic islets isolated from Rip-Ins1-Ifnarfl/fl and Rip-Ins1-Ifnarfl/wt mice. Islets were cultured in the presence of IFN-β (100 U/ml) for 12 hours prior to RNA extraction. (B) Blood glucose levels and T1D incidence over a 15-day postinfection period. (C) Representative H&E images (20× magnification) of the pancreatic islets from Rip-Ins1-Ifnarfl/fl and Rip-Ins1-Ifnarfl/wt mice at day 15 p.i. (D) Pancreata were isolated at day 5 p.i. from Rip-GP mice infected i.p. with 2 × 105 PFU LCMV or 2 × 105 LCMV-GPV. Half pancreata was stained via immunofluorescence with antibody to insulin and F4/80 (40× magnification). Macrophages were examined in the second half of pancreatic tissue by flow cytometry by gating on CD45+F4/80+ cells. (E) Frequency of CD11b+ cells in the spleens and PLNs of clodronate liposome–treated mice at day 3 after LCMV infection. qPCR analysis was performed on RNA isolated from islets of 3 mice per group. Fold change in gene expression was relative to islets treated with vehicle control (PBS). Data are presented as average ± SEM; statistical significance was measured using an unpaired 2-tailed Student t test or 1-way ANOVA analysis. Statistical significant of T1D disease incidence was measured using a log-rank (Mantel-Cox) test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.