Slc11a1 enhances the autoimmune diabetogenic T-cell response by altering processing and presentation of pancreatic islet antigens.
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.


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)-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 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.
Dai
Yang D
YD
Division of Immune Regulation, Torrey Pines Institute for Molecular Studies, San Diego, California, USA. ydai@tpims.org
Marrero
Idania G
IG
Gros
Philippe
P
Zaghouani
Habib
H
Wicker
Linda S
LS
Sercarz
Eli E
EE
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D018122:B7-1 Antigen / Q000378:metabolism; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010587:Phagocytosis / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D000099173:Natural Resistance-associated Macrophage Protein 1
D018122:B7-1 Antigen; D027682:Cation Transport Proteins; D000949:Histocompatibility Antigens Class II; D000099173:Natural Resistance-associated Macrophage Protein 1