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Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes

Abstract

Type 1 diabetes develops over many years and is characterized ultimately by the destruction of insulin-producing pancreatic beta cells by autoreactive T cells. Nonetheless, the role of innate cells in the initiation of this disease remains poorly understood. Here, we show that in young female nonobese diabetic mice, physiological beta cell death induces the recruitment and activation of B-1a cells, neutrophils and plasmacytoid dendritic cells (pDCs) to the pancreas. Activated B-1a cells secrete IgGs specific for double-stranded DNA. IgGs activate neutrophils to release DNA-binding cathelicidin-related antimicrobial peptide (CRAMP), which binds self DNA. Then, self DNA, DNA-specific IgG and CRAMP peptide activate pDCs through the Toll-like receptor 9–myeloid differentiation factor 88 pathway, leading to interferon-α production in pancreatic islets. We further demonstrate through the use of depleting treatments that B-1a cells, neutrophils and IFN-α–producing pDCs are required for the initiation of the diabetogenic T cell response and type 1 diabetes development. These findings reveal that an innate immune cell crosstalk takes place in the pancreas of young NOD mice and leads to the initiation of T1D.

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Figure 1: Innate immune cells infiltrate the pancreas of NOD mice in the first postnatal weeks.
Figure 2: Pancreatic pDCs express IFN-α and are required for T1D development in NOD mice.
Figure 3: B-1a cells activate pDCs in the pancreas and participate in the initiation of T1D.
Figure 4: Neutrophils from the pancreas of young NOD mice produce NET-associated CRAMP at 3 weeks of age.
Figure 5: Neutrophils and B-1a cells cooperate to promote IFN-α production by pDCs.
Figure 6: Initial beta cell death is required to induce innate cell activation and T1D development.

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Acknowledgements

We thank N. Charles (INSERM UMR-S 699, Paris Diderot University) for dsDNA-specific immunoglobulin ELISA, M. Colonna (Department of Pathology and Immunology, Washington University School of Medicine) for m927 mAb, S. Mecheri (Biology of Host Parasite Interactions Unit, Pasteur Institute) for NIMP-14 mAb, S. Muller (CNRS, Institut de Biologie Moléculaire et Cellulaire, UPR9021) for serum from NZB/W F1 mice, J. Ravetch (Laboratory of Molecular Genetics and Immunology, Rockefeller University) for FcγRIV-specific mAb, N. Thieblemont (CNRS UMR 8147, Paris Descartes University) for Myd88−/− NOD mice and all for their expertise. We thank F. Boutillon for technical assistance and the staff of the INSERM U986 mouse facility for help in animal care. Y.S. is supported by a doctoral fellowship from the Region Ile de France. This work was supported by funds from INSERM, Centre National de la Recherche Scientifique, ANR-05-PCOD009-01, ANR-09-GENO-023 and Labex INFLAMEX to A.L. A.L. is recipient of an APHP-CNRS Contrat Hospitalier de Recherche Translationelle.

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J.D. initiated and led the whole project, coordinated with different investigators, designed and performed experiments, analyzed the data and wrote the manuscript; Y.S. designed and performed experiments, analyzed the data and wrote the manuscript; L.F. did confocal microscopy experiments, analyzed the data and wrote the manuscript; L.B. provided technical assistance; B.A. and F.B. provided intellectual input and key reagents for neutrophil and pDC analysis; and A.L. was responsible for project planning, data analysis, discussion and writing.

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Correspondence to Julien Diana or Agnès Lehuen.

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Diana, J., Simoni, Y., Furio, L. et al. Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes. Nat Med 19, 65–73 (2013). https://doi.org/10.1038/nm.3042

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