TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells

• Published in: Nature medicine Vol. 11; no. 6; pp. 653 - 660
• Main Authors: Modlin, Robert L, Krutzik, Stephan R, Tan, Belinda, Li, Huiying, Ochoa, Maria Teresa, Liu, Philip T, Sharfstein, Sarah E, Graeber, Thomas G, Sieling, Peter A, Liu, Yong-Jun, Rea, Thomas H, Bloom, Barry R
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01-06-2005
• Subjects: Antigens, CD1 - metabolism; Cell Adhesion Molecules - metabolism; Cell Differentiation - physiology; Dendritic Cells - physiology; Gene Expression; Humans; Immune system; Immunity, Innate - physiology; Infectious diseases; Lectins, C-Type - metabolism; Leprosy - immunology; Lesions; Lymphocyte Activation; Macrophages - physiology; Membrane Glycoproteins - physiology; Monocytes - physiology; Receptors, Cell Surface - metabolism; Receptors, Cell Surface - physiology; T-Lymphocytes - physiology; Toll-Like Receptors
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm1246

Leprosy enables investigation of mechanisms by which the innate immune system contributes to host defense against infection, because in one form, the disease progresses, and in the other, the infection is limited. We report that Toll-like receptor (TLR) activation of human monocytes induces rapid differentiation into two distinct subsets: DC-SIGN+ CD16+ macrophages and CD1b+ DC-SIGN- dendritic cells. DC-SIGN+ phagocytic macrophages were expanded by TLR-mediated upregulation of interleukin (IL)-15 and IL-15 receptor. CD1b+ dendritic cells were expanded by TLR-mediated upregulation of granulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor, promoted T cell activation and secreted proinflammatory cytokines. Whereas DC-SIGN+ macrophages were detected in lesions and after TLR activation in all leprosy patients, CD1b+ dendritic cells were not detected in lesions or after TLR activation of peripheral monocytes in individuals with the progressive lepromatous form, except during reversal reactions in which bacilli were cleared by T helper type 1 (TH1) responses. In tuberculoid lepromatous lesions, DC-SIGN+ cells were positive for macrophage markers, but negative for dendritic cell markers. Thus, TLR-induced differentiation of monocytes into either macrophages or dendritic cells seems to crucially influence effective host defenses in human infectious disease.