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Department of Microbiology and Immunology and Robarts Research Institute, University of Western Ontario, London, Ontario, Canada
Despite the pivotal role of dendritic cells (DC) in shaping immunity, little is known about their functionality in type 1 diabetes. Moreover, due to the paucity of DC in vivo, functional studies have relied largely upon in vitro-expanded cells to elucidate type 1 diabetes-associated functional abnormalities. In this study, we provide a comprehensive analysis of the functional capabilities of in vivo-derived DC subsets from NOD mice by comparing DC to other NOD APC types and to DC from autoimmune-resistant strains. NOD DC closely resemble those from nonautoimmune strains with respect to costimulation and cytokine production. The exception is the CD8
+CD11b–DC subset which is numerically reduced in NOD spleens, but not in the pancreatic lymph nodes, while DC from both tissues produce little IL-12 in this strain. This defect results in unusual deferral toward macrophage-derived IL-12 in NOD mice; NOD macrophages produce aberrantly high IL-12 levels that can overcompensate for the DC defect in Th1 polarization. APC subset use for autoantigen presentation also differs in NOD mice. NOD B cells overshadow DC at activating islet-reactive T cells, whereas DC and B cells in NOD-resistant mice are functionally comparable. Differential involvement of APC subsets in T cell activation and tolerance induction may prove to be a crucial factor in the selection and expansion of autoreactive T cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Canadian Institutes of Health Research. A.M.M. was a recipient of a doctoral award from the Canadian Institutes of Health Research.
2 Current address: Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037.
3 Current address: Lawson Health Research Institute, London, Ontario, Canada, N6A 4V2.
4 Address correspondence and reprint requests to Dr. Bhagirath Singh, Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada, N6A 5C1. E-mail address: bsingh{at}uwo.ca
5 Abbreviations used in this paper: T1D, type 1 diabetes; DC, dendritic cell; BM, bone marrow; NOR, NOD resistant; PI, propidium iodide; PLN, pancreatic lymph node; GAD, glutamic acid decarboxylase.
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