Slc11a1, formerly Nramp1, is expressed in dendritic cells and influences major histocompatibility complex class II expression and antigen-presenting cell function.
Solute carrier family 11 member a1 (Slc11a1; formerly Nramp1) encodes a late endosomal/lysosomal protein/divalent cation transporter that regulates iron homeostasis in macrophages. During macrophage activation, Slc11a1 has multiple pleiotropic effects on gene regulation and function, including gamma interferon-induced class II expression and antigen-presenting cell function. The wild-type allele at Slc11a1 has been associated with a bias in Th1 cell function in vivo, which is beneficial in resistance to infection against intracellular macrophage pathogens but detrimental in contributing to development of type 1 diabetes. The extent to which this depends on macrophage versus dendritic cell (DC) function is not known. Here we show that Slc11a1 is expressed in late endosomes and/or lysosomes of CD11c(+) DCs. DCs from mutant and congenic wild-type mice upregulate interleukin-12 (IL-12) and IL-10 mRNA in response to lipopolysaccharide (LPS) stimulation, but the ratio of IL-10 to IL-12 is higher in unstimulated DCs and DCs stimulated for 15 h with LPS from mutant mice than from wild-type mice. DCs from wild-type mice upregulate major histocompatibility complex class II in response to LPS more efficiently than DCs from mutant mice. Unstimulated DCs from wild-type and mutant mice present ovalbumin (OVA) peptide with an efficiency equivalent to that of an OVA-specific CD4 T-cell line, but DCs from wild-type mice are more efficient at processing and presenting OVA or Leishmania activator of cell kinase (LACK) protein to OVA- and LACK-specific T cells. These data indicate that wild-type Slc11a1 expressed in DCs may play a role both in determining resistance to infectious disease and in susceptibility to autoimmune disease such as type 1 diabetes.
Stober
Carmel B
CB
Cambridge Institute for Medical Research and Department of Medicine, Wellcome Trust/MRC Building, University of Cambridge School of Clinical Medicine, Addenbrookes Hospital, Hills Road, Cambridge CB2 2XY, United Kingdom.
Brode
Sven
S
White
Jacqueline K
JK
Popoff
Jean-François
JF
Blackwell
Jenefer M
JM
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000953:Antigens, Protozoan / Q000276:immunology; D015982:Bias; D027682:Cation Transport Proteins / Q000096:biosynthesis* / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000737:chemistry / Q000276:immunology*; D011992:Endosomes / Q000737:chemistry; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics; D007891:Leishmania; D008070:Lipopolysaccharides / Q000276:immunology; D008247:Lysosomes / Q000737:chemistry; D008285:Major Histocompatibility Complex; D051379:Mice; D008817:Mice, Mutant Strains; D018613:Microscopy, Confocal; D010047:Ovalbumin / Q000276:immunology; D015800:Protozoan Proteins / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099173:Natural Resistance-associated Macrophage Protein 1
D000953:Antigens, Protozoan; D027682:Cation Transport Proteins; D000949:Histocompatibility Antigens Class II; D016753:Interleukin-10; D018664:Interleukin-12; D008070:Lipopolysaccharides; D010047:Ovalbumin; D015800:Protozoan Proteins; D012333:RNA, Messenger; D000099173:Natural Resistance-associated Macrophage Protein 1; C093139:LACK antigen, Leishmania