Slc11a1, Formerly Nramp1, Is Expressed in Dendritic Cells and Influences Major Histocompatibility Complex Class II Expression and Antigen-Presenting Cell Function

• Published in: Infection and Immunity 2007-10, Vol.75 (10), p.5059-5067
• Main Authors: Stober, Carmel B, Brode, Sven, White, Jacqueline K, Popoff, Jean-François, Blackwell, Jenefer M
• Format: Article
• Language: English
• Subjects: Animals; Antigen Presentation - immunology; Antigens, Protozoan - immunology; Bias; Biological and medical sciences; Cation Transport Proteins - biosynthesis; Cation Transport Proteins - immunology; Cells, Cultured; Dendritic Cells - chemistry; Dendritic Cells - immunology; Endosomes - chemistry; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Regulation; Histocompatibility Antigens Class II - biosynthesis; Histocompatibility Antigens Class II - immunology; Host Response and Inflammation; Interleukin-10 - biosynthesis; Interleukin-10 - genetics; Interleukin-12 - biosynthesis; Interleukin-12 - genetics; Leishmania; Lipopolysaccharides - immunology; Lysosomes - chemistry; Major Histocompatibility Complex; Mice; Mice, Mutant Strains; Microscopy, Confocal; Ovalbumin - immunology; Protozoan Proteins - immunology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; RNA, Messenger - genetics
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00153-07

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.