Macrophages present exogenous antigens by class I major histocompatibility complex molecules via a secretory pathway as a consequence of interferon-gamma activation.
Macrophages can process and present exogenous antigens on major histocompatibility complex (MHC) class I molecules through an alternative mechanism involving the internalization of antigens and the secretion of peptides loading MHC class I molecules at the cell surface. In this paper, we found that interferon-gamma (IFN-gamma) -activated macrophages infected with Salmonella typhimurum secreted peptides able to load empty MHC Kb molecules on co-cultured TAP-2-deficient RMA-S cells, added as targets for peptide loading. The increase in class I Kb on the RMA-S cells, resulting from the macrophage-derived peptides, exhibited a comparable stability as the direct addition of an exogenous Kb-binding peptide (OVA257-264) to the RMA-S cells. In both cases, the Kb complexes were stable for at least 3 hr after separating the RMA-S cells from the macrophages. The endosomal inhibitors, leupeptin and ammonium chloride, did not inhibit the release of peptides and the increase in Kb staining on the RMA-S cells in the co-culture systems. Brefeldin A also had no effect. P815 cells previously co-cultured with Salmonella-infected macrophages became targets for cytotoxic T lymphocytes isolated from Salmonella-infected BALB/c mice. Taken together, our data suggest that IFN-gamma-activated macrophages process exogenous antigens in an intracellular compartment where serine proteases generate peptides released to the external environment for loading empty MHC class I molecules at the cell surface. This TAP-independent mechanism for the MHC class I presentation may be involved in priming cytotoxic T lymphocytes against intracellular pathogens in vivo.
Martín-Orozco
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N
Unidad de Investigación Medica en Inmunoquímica, Hospital de Especialidades, Centro Medico Nacional SXXI Instituto Mexicano del Seguro Social, Mexico.
Isibasi
A
A
Ortiz-Navarrete
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V
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D020126:Brefeldin A / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018929:Cell Culture Techniques; D011992:Endosomes / Q000276:immunology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology*; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010455:Peptides / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012480:Salmonella Infections / Q000276:immunology; D012486:Salmonella typhimurium
D015395:Histocompatibility Antigens Class I; D010455:Peptides; D011500:Protein Synthesis Inhibitors; D020126:Brefeldin A; D007371:Interferon-gamma