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 2

Clodronate liposome–induced depletion of macrophages prevents T1D disease.

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Clodronate liposome–induced depletion of macrophages prevents T1D diseas...
(A) Blood glucose levels of clodronate treated mice during a 54-day observation period. (B) Immunofluorescence inspection of (40× magnification) LCMV-GP33–41–specific CD8+ P14 T cells and F4/80+ macrophages in the islets of clodronate or PBS liposome–treated mice at day 6 p.i. Yellow outlines represent islet boundaries, and yellow arrows show P14 CD8+ T cells. (C) Examination of P14 CD8+ T cells in the spleen and pancreatic lymph nodes (PLN) of clodronate liposome–treated mice at day 6 p.i. using flow cytometry. (D) Frequency of LCMV-GP33–41 tetramer–positive and LCMV396–404 tetramer–positive CD8+ T cells in the spleens of clodronate treated mice at day 8 p.i. (E) Viral titers in the sera were measured by plaque assay over a 53-day post-infection period. (F) Anti–LCMV-NP staining (20× magnification) of pancreatic tissue from clodronate-treated mice at days 15 and 53 p.i. Yellow outlines depict islet boundaries. Flow cytometry data of P14 T cells represents at least 4 mice per group. Immunofluorescence analysis of islet-infiltrating T cells is an average of at least 8 islets per mouse and a total of 4 mice per group. Statistical significance was measured using 1-way ANOVA. Data are presented as average ± SEM. *P < 0.05, ****P < 0.0001