Abstract

Objective. Efforts to map non-MHC genes causing type 1 diabetes (T1D) 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). Since DCs are antigen presenting cells (APC) known to be critically involved in the immunopathogenic events leading to T1D, 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 glutamic acid decarboxylase (GAD) -65, and its function contributed to the activation of a pathogenic T cell clone, BDC2.5. An enhanced generation of 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.

Conclusions. The association of variants encoding Slc11a1 with T1D 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.