Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature Medicine volume 11, pages 653–660 (2005)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: DC-SIGN and CD1b are expressed on distinct subsets of cells and are induced by TLR activation.
Figure 2: IL-15 and GM-CSF induce monocyte differentiation.
Figure 3: DC-SIGN+ cells have a macrophage phenotype whereas CD1b+ cells have a dendritic cell phenotype.
Figure 4: DC-SIGN+ macrophages bind and phagocytose mycobacteria.
Figure 5: CD1b+ dendritic cells produce cytokines and are potent T-cell activators.
Figure 6: Macrophage and dendritic cell subsets in leprosy.

Similar content being viewed by others

References

  1. Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J.M., & Hoffmann, J.A. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86, 973–983 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Takeuchi, O., Hoshino, K., & Akira, S. Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to staphylococcus aureus infection. J. Immunol. 165, 5392–5396 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. O'Brien, A.D. et al. Genetic control of susceptibility to Salmonella typhimurium in mice: role of the LPS gene. J. Immunol. 124, 20–24 (1980).

    CAS  PubMed  Google Scholar 

  4. Alexopoulou, L. et al. Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in. Nat. Med. 8, 878–884 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Krutzik, S.R. et al. Activation and regulation of Toll-like receptors 2 and 1 in human leprosy. Nat. Med. 9, 525–532 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Blander, J.M. & Medzhitov, R. Regulation of phagosome maturation by signals from toll-like receptors. Science 304, 1014–1018 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Doyle, S.E. et al. Toll-like receptors induce a phagocytic gene program through p38. J. Exp. Med. 199, 81–90 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Thoma-Uszynski, S. et al. Induction of direct antimicrobial activity through mammalian toll-like receptors. Science 291, 1544–1547 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Medzhitov, R., Preston-Hurlburt, P. & Janeway, C.A.J. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394–397 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Brightbill, H.D. et al. Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285, 732–736 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Hertz, C.J. et al. Microbial lipopeptides stimulate dendritic cell maturation via TLR2. J. Immunol. 166, 2444–2450 (2000).

    Article  Google Scholar 

  12. Porcelli, S.A. & Modlin, R.L. The CD1 system: antigen-presenting molecules for T cell recognition of lipids and glycolipids. Annu. Rev. Immunol. 17, 297–329 (1999).

    Article  CAS  PubMed  Google Scholar 

  13. Beckman, E.M. et al. Recognition of a lipid antigen by CD1-restricted αβ+ T cells. Nature 372, 691–694 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. Sieling, P.A. et al. CD1-restricted T cell recognition of microbial lipoglycans. Science 269, 227–230 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Moody, D.B. et al. Structural requirements for glycolipid antigen recognition by CD1b-restricted T cells. Science 278, 283–286 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Engering, A. et al. The dendritic cell-specific adhesion receptor DC-SIGN internalizes antigen for presentation to T cells. J. Immunol. 168, 2118–2126 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Geijtenbeek, T.B. et al. Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100, 575–585 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Geijtenbeek, T.B. et al. Mycobacteria target DC-SIGN to suppress dendritic cell function. J. Exp. Med. 197, 7–17 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tailleux, L. et al. DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells. J. Exp. Med. 197, 121–127 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Appelmelk, B.J. et al. Cutting edge: carbohydrate profiling identifies new pathogens that interact with dendritic cell-specific ICAM-3-grabbing nonintegrin on dendritic cells. J. Immunol. 170, 1635–1639 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Cambi, A. et al. The C-type lectin DC-SIGN (CD209) is an antigen-uptake receptor for Candida albicans on dendritic cells. Eur. J. Immunol. 33, 532–538 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Colmenares, M., Puig-Kroger, A., Pello, O.M., Corbi, A.L. & Rivas, L. Dendritic cell (DC)-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN, CD209), a C-type surface lectin in human DCs, is a receptor for Leishmania amastigotes . J. Biol. Chem. 277, 36766–36769 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Wemambu, S.N.C., Turk, J.L., Waters, M.F.R. & Rees, R.J.W. Erythema nodosum leprosum: a clinical manifestation of the Arthus phenomenon. Lancet 2, 933–935 (1969).

    Article  CAS  PubMed  Google Scholar 

  24. Salgame, P. et al. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science 254, 279–282 (1991).

    Article  CAS  PubMed  Google Scholar 

  25. Yamamura, M. et al. Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science 254, 277–279 (1991).

    Article  CAS  PubMed  Google Scholar 

  26. Yamamura, M. et al. Cytokine patterns of immunologically mediated tissue damage. J. Immunol. 149, 1470–1475 (1992).

    CAS  PubMed  Google Scholar 

  27. Kadowaki, N. et al. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J. Exp. Med. 194, 863–869 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Graeber, T.G. & Eisenberg, D. Bioinformatic identification of potential autocrine signaling loops in cancers from gene expression profiles. Nat. Genet. 29, 295–300 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Ochoa, M.T. et al. T-cell release of granulysin contributes to host defense in leprosy. Nat. Med. 7, 174–179 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Soilleux, E.J. et al. Constitutive and induced expression of DC-SIGN on dendritic cell and macrophage subpopulations in situ and in vitro . J. Leukoc. Biol 71, 445–457 (2002).

    CAS  PubMed  Google Scholar 

  31. Chehimi, J. et al. HIV-1 transmission and cytokine-induced expression of DC-SIGN in human monocyte-derived macrophages. J. Leukoc. Biol. 74, 757–763 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. van Lent, P.L. et al. Expression of the dendritic cell-associated C-type lectin DC-SIGN by inflammatory matrix metalloproteinase-producing macrophages in rheumatoid arthritis synovium and interaction with intercellular adhesion molecule 3-positive T cells. Arthritis Rheum. 48, 360–369 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Giordano, D., Magaletti, D.M., Clark, E.A., & Beavo, J.A. Cyclic nucleotides promote monocyte differentiation toward a DC-SIGN+ (CD209) intermediate cell and impair differentiation into dendritic cells. J. Immunol. 171, 6421–6430 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Geijtenbeek, T.B. et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100, 587–597 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Relloso, M. et al. DC-SIGN (CD209) expression is IL-4 dependent and is negatively regulated by IFN, TGF-beta, and anti-inflammatory agents. J. Immunol. 168, 2634–2643 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Judge, A.D., Zhang, X., Fujii, H., Surh, C.D. & Sprent, J. Interleukin 15 controls both proliferation and survival of a subset of memory-phenotype CD8(+) T cells. J. Exp. Med. 196, 935–946 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Schluns, K.S., Williams, K., Ma, A., Zheng, X.X. & Lefrancois, L. Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J. Immunol. 168, 4827–4831 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Pulendran, B. et al. Dendritic cells generated in the presence of GM-CSF plus IL-15 prime potent CD8+ Tc1 responses in vivo . Eur. J. Immunol. 34, 66–73 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Hirschfeld, M., Ma, Y., Weis, J.H., Vogel, S.N., & Weis, J.J. Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and murine toll-like receptor 2. J. Immunol. 165, 618–622 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Takeuchi, O. et al. Cutting edge: Preferentially the R-stereoisomer of the mycoplasmal lipopeptide macrophage-activating lipopeptide-2 activates immune cells through a toll-like receptor 2- and MyD88-dependent signaling pathway. J. Immunol. 164, 554–557 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Ridley, D.S. & Jopling, W.H. Classification of leprosy according to immunity. A five-group system. Int. J. Lepr. 34, 255–273 (1966).

    CAS  Google Scholar 

  42. Kim, J. et al. Determinants of T cell reactivity to the Mycobacterium leprae GroES homologue. J. Immunol. 159, 335–343 (1997).

    CAS  PubMed  Google Scholar 

  43. Stenger, S. et al. An antimicrobial activity of cytolytic T cells mediated by granulysin. Science 282, 121–125 (1998).

    Article  CAS  PubMed  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  1. Division of Dermatology, UCLA, 611 Charles Young Drive East, 536 Boyer Hall, Los Angeles, 90095, California, USA

    Stephan R Krutzik, Belinda Tan, Maria Teresa Ochoa, Sarah E Sharfstein, Peter A Sieling & Robert L Modlin

  2. Department of Microbiology and Immunology, David Geffen School of Medicine at UCLA, 611 Charles Young Drive East, 536 Boyer Hall, Los Angeles, 90095, California, USA

    Stephan R Krutzik, Belinda Tan, Philip T Liu & Robert L Modlin

  3. Department of Chemistry and Biochemistry, UCLA-Department of Energy Institute of Genomics and Proteomics, UCLA, 611 Charles Young Drive East, 536 Boyer Hall, Los Angeles, 90095, California, USA

    Huiying Li & Thomas G Graeber

  4. Department of Immunology and Center for Cancer Immunology Research, M.D. Anderson Cancer Center, University of Texas, 1515 Holcombe Boulevard, Houston, 77030, Texas, USA

    Yong-Jun Liu

  5. Section of Dermatology, University of Southern California School of Medicine, 2020 Zonal Avenue, IRD 620, Los Angeles, 90033, California, USA

    Thomas H Rea

  6. Office of the Dean, Harvard School of Public Health, 677 Huntington Avenue, Kresge Building 1005, Boston, 02115, Massachusetts, USA

    Barry R Bloom

Authors
  1. Stephan R Krutzik
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Belinda Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huiying Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria Teresa Ochoa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Philip T Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sarah E Sharfstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Thomas G Graeber
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peter A Sieling
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yong-Jun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Thomas H Rea
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Barry R Bloom
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Robert L Modlin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert L Modlin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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)

Supplementary Note (PDF 11 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1246

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing