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* Diabetes Research Center, Division of Endocrinology and
Division of Molecular Immunology, Department of Pediatrics, Cincinnati Children’s Research Foundation and the University of Cincinnati College of Medicine, Cincinnati OH 45229; and
Immunotherapy Center, Medical College of Georgia, Augusta, GA 30912
Islet Ag-specific CD4+ T cells receive antigenic stimulation from MHC class II-expressing APCs. Herein, we delineate the direct in vivo necessity for distinct subsets of macrophages and dendritic cells (DC) in type 1 diabetes mellitus of the NOD mouse by using diphtheria toxin-mediated cell ablation. The ablation of macrophages had no impact on islet Ag presentation or on the induction of insulitis or diabetes in either transfer or spontaneous models. However, the ablation of CD11b+CD11c+ DC led to the loss of T cell activation, insulitis, and diabetes mediated by CD4+ T cells. When the specific myeloid DC subset was "added-back" to mice lacking total DC, insulitis and diabetes were restored. Interestingly, when NOD mice were allowed to progress to the insulitis phase, the ablation of DC led to accelerated insulitis. This accelerated insulitis was mediated by the loss of plasmacytoid DC (pDC). When pDC were returned to depleted mice, the localized regulation of insulitis was restored. The loss of pDC in the pancreas itself was accompanied by the localized loss of IDO and the acceleration of insulitis. Thus, CD11c+CD11b+ DC and pDC have countervailing actions in NOD diabetes, with myeloid DC providing critical antigenic stimulation to naive CD4+ T cells and pDC providing regulatory control of CD4+ T cell function in the target tissue.
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1 This work is supported in part by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK62274) and Juvenile Diabetes Research Foundation (1-2002-142) and by Diabetes Campaign Funds from the Diabetes Research Center at the Cincinnati Children’s Research Foundation. J.K.O. is a recipient of a Juvenile Diabetes Research Foundation postdoctoral fellowship (3-2006-615).
2 Address correspondence and reprint requests to Dr. Jonathan D. Katz, Cincinnati Children’s Research Foundation, 3333 Burnet Avenue, Room 1409, Cincinnati, OH 45229. E-mail address: jonathan.katz{at}cchmc.org
3 Abbreviations used in this paper: T1DM, type 1 diabetes mellitus; BM, bone marrow; DC, dendritic cell; DT, diphtheria toxin; DTR, human diphtheria toxin receptor; mDC, myeloid dendritic cell; lyDC, lymphoid dendritic cells; 1-MT, 1-methyl-D-tryptophan; NKT, NK T (cell); pDC, plasmacytoid dendritic cell; PCDA-1, pDC Ag-1; PLN, pancreatic lymph node; Treg, regulatory T (cell).
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