Slc11a1 Enhances the Autoimmune Diabetogenic T-Cell Response by Altering Processing and Presentation of Pancreatic Islet Antigens

Slc11a1 Enhances the Autoimmune Diabetogenic T-Cell Response by Altering Processing and Presentation of Pancreatic Islet Antigens Yang D. Dai 1 , Idania G. Marrero 1 , Philippe Gros 2 , Habib Zaghouani 3 , Linda S. Wicker 4 and Eli E. Sercarz 1 1 Division of Immune Regulation, Torrey Pines Institute for Molecular Studies, San Diego, California 2 Department of Biochemistry, McGill University, Montreal, Canada 3 Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, Missouri 4 Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K Corresponding author: Yang D. Dai, ydai{at}tpims.org , or Eli E. Sercarz, esercarz{at}tpims.org Abstract OBJECTIVE— 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. RESEARCH DESIGN AND METHODS— 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. RESULTS— 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)-γ–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. CONCLUSIONS— 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. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 4 November 2008. Readers may use this article as long as the work is properly cited, the use is educational