Abstract
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.
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Acknowledgements
We would like to thank P. Brennan (Colorado State University and NIAID Contract NO1 AI-75320) for the gift of the M. leprae bacterioferritin major membrane protein II (MMPII) monoclonal antibody. We would also like to thank K. Grossheider for her technical help. This work was supported in part by grants from the US National Institutes of Health (AI07126, AI22553, AI47866).
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Supplementary information
Supplementary Fig. 1
TLR2/1 activation triggers the modulation of an additional 5 ligand/receptor signaling pairs. (PDF 141 kb)
Supplementary Fig. 2
Activation via TLR2/1 with the tri-acylated Pam3CSK4 lipopeptide triggers monocyte differentiation in a pattern identical to the mycobacterial 19-kDa lipopeptide. (PDF 158 kb)
Supplementary Fig. 3
Peripheral monocytes from L-lep patients do not have a deficiency in responding to recombinant GM-CSF and expressing CD1b. (PDF 59 kb)
Supplementary Fig. 4
Analysis of DC-SIGN+ cells in human tonsil reveals a pattern similar to that found in T-lep lesions. (PDF 152 kb)
Supplementary Fig. 5
Toll-like receptor activation leads to the differentiation of monocytes into dendritic cells, with antigen presentation function, and macrophages, with phagocytic capacity. (PDF 113 kb)
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Krutzik, S., Tan, B., Li, H. et al. TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells. Nat Med 11, 653–660 (2005). https://doi.org/10.1038/nm1246
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DOI: https://doi.org/10.1038/nm1246
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