Essential roles of insulin expression in Aire+ tolerogenic dendritic cells in maintaining peripheral self-tolerance of islet β-cells.
Anti-insulin autoimmunity is one of the primary forces in initiating and progressing β-cell destruction in type 1 diabetes. While insulin expression in thymic medullary epithelial cells has been shown to be essential for establishing β-cell central tolerance, the function of insulin expression in antigen-presenting cells (APCs) of hematopoietic lineage remains elusive. With a Cre-lox reporter approach, we labeled Aire-expressing cells with enhanced yellow fluorescent proteins, and found that insulin expression in the spleen was restricted predominantly to a population of Aire(+)CD11c(int)B220(+) dendritic cells (DCs). Targeted insulin deletion in APCs failed to induce anti-islet autoimmunity in B6 mice. In contrast, elevated levels of T cell infiltration into islets were observed in B6(g7) congenic mice when insulin was specifically deleted in their CD11c-expressing DCs (B6(g7)·CD11c-ΔIns mice). Thus, insulin expression in BM-derived, Aire(+) tolerogenic DCs may play an essential role to prevent the activation and expansion of insulin-reactive T cells in the periphery.
Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, PA, USA.
Maria
M
Grupillo
Giulio
G
Gualtierotti
Jing
J
He
Giorgia
G
Sisino
Rita
R
Bottino
William A
WA
Rudert
Massimo
M
Trucco
Yong
Y
Fan
D000818:Animals; D015551:Autoimmunity; D001426:Bacterial Proteins / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D017930:Genes, Reporter; D007328:Insulin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020556:Neutrophil Infiltration; D061166:Peripheral Tolerance; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000096927:AIRE Protein
D001426:Bacterial Proteins; D007328:Insulin; D008164:Luminescent Proteins; D014157:Transcription Factors; D000096927:AIRE Protein; C054562:yellow fluorescent protein, Bacteria