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Efforts to map non-major histocompatibility complex (MHC) genes causing type 1 diabetes in NOD mice identified Slc11a1, formerly Nramp1, as the leading candidate gene in the Idd5.2 region. Slc11a1 is a membrane transporter of bivalent cations that is expressed in late endosomes and lysosomes of macrophages and dendritic cells (DCs). Because DCs are antigen-presenting cells (APCs) known to be critically involved in the immunopathogenic events leading to type 1 diabetes, we hypothesized that Slc11a1 alters the processing or presentation of islet-derived antigens to T-cells.NOD mice having wild-type (WT) or mutant Slc11a1 molecules and 129 mice having WT or null Slc11a1 alleles were examined for parameters associated with antigen presentation.We found that Slc11a1 enhanced the presentation of a diabetes-related T-cell determinant of GAD65, and its function contributed to the activation of a pathogenic T-cell clone, BDC2.5. An enhanced generation of interferon (IFN)-gamma-producing T-cells was also associated with functional Slc11a1. The alteration of immune responsiveness by Slc11a1 genotype did not correlate with altered MHC class II expression in DCs; however, functional Slc11a1 was associated with accelerated phagocytosis and phagosomal acidification in DCs.The association of variants encoding Slc11a1 with type 1 diabetes may reflect its function in processing and presentation of islet self-antigens in DCs. Thus, non-MHC genes could affect the MHC-restricted T-cell response through altered antigen processing and presentation.

Original publication

DOI

10.2337/db07-1608

Type

Journal article

Journal

Diabetes

Publication Date

01/2009

Volume

58

Pages

156 - 164

Addresses

Division of Immune Regulation, Torrey Pines Institute for Molecular Studies, San Diego, California, USA. ydai@tpims.org

Keywords

Islets of Langerhans, Dendritic Cells, T-Lymphocytes, Cells, Cultured, Macrophages, Animals, Mice, Inbred NOD, Mice, Knockout, Mice, Diabetes Mellitus, Type 1, Cation Transport Proteins, Histocompatibility Antigens Class II, Blotting, Western, Flow Cytometry, Cell Proliferation, Phagocytosis, Autoimmunity, Antigen Presentation, B7-1 Antigen