Activation of the innate immune receptor Dectin-1 upon formation of a ‘phagocytic synapse’ (original) (raw)

Nature volume 472, pages 471–475 (2011)Cite this article

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Abstract

Innate immune cells must be able to distinguish between direct binding to microbes and detection of components shed from the surface of microbes located at a distance. Dectin-1 (also known as CLEC7A) is a pattern-recognition receptor expressed by myeloid phagocytes (macrophages, dendritic cells and neutrophils) that detects β-glucans in fungal cell walls and triggers direct cellular antimicrobial activity, including phagocytosis and production of reactive oxygen species (ROS)1,2. In contrast to inflammatory responses stimulated upon detection of soluble ligands by other pattern-recognition receptors, such as Toll-like receptors (TLRs), these responses are only useful when a cell comes into direct contact with a microbe and must not be spuriously activated by soluble stimuli. In this study we show that, despite its ability to bind both soluble and particulate β-glucan polymers, Dectin-1 signalling is only activated by particulate β-glucans, which cluster the receptor in synapse-like structures from which regulatory tyrosine phosphatases CD45 and CD148 (also known as PTPRC and PTPRJ, respectively) are excluded (Supplementary Fig. 1). The ‘phagocytic synapse’ now provides a model mechanism by which innate immune receptors can distinguish direct microbial contact from detection of microbes at a distance, thereby initiating direct cellular antimicrobial responses only when they are required.

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Acknowledgements

We thank K. Wawrowsky for help with confocal microscopy, and G. D. Brown for Dectin-1-deficient mice. This study was funded by grants from the NIH (AI071116 and AI066120 to D.M.U. and A.W., respectively) and the American Heart Association (D.M.U.). H.S.G. held a Research Fellowship Award from the Crohn’s and Colitis Foundation of America. D.M.U. holds the Janis and William Wetsman Family Chair in Inflammatory Bowel Disease at Cedars-Sinai Medical Center.

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Authors and Affiliations

  1. IBD and Immunobiology Research Institute, 8700 Beverly Boulevard, Cedars-Sinai Medical Center, Los Angeles, 90048, California, USA
    Helen S. Goodridge, Christopher N. Reyes, Courtney A. Becker, Jun Ma, Andrea J. Wolf & David M. Underhill
  2. Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, 90048, California, USA
    Helen S. Goodridge
  3. David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, University of California, Los Angeles, 90095, California, USA
    Helen S. Goodridge & David M. Underhill
  4. Department of Medicine, Rosalind Russell Medical Research Center for Arthritis, 513 Parnassus, University of California, San Francisco, 94143, California, USA
    Tamiko R. Katsumoto & Arthur Weiss
  5. Biothera, 3388 Mike Collins Drive, Eagan, 55121, Minnesota, USA
    Nandita Bose, Anissa S. H. Chan, Andrew S. Magee, Michael E. Danielson & John P. Vasilakos
  6. Howard Hughes Medical Institute, University of California, San Francisco, 94143, California, USA
    Arthur Weiss

Authors

  1. Helen S. Goodridge
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  2. Christopher N. Reyes
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  3. Courtney A. Becker
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  4. Tamiko R. Katsumoto
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  5. Jun Ma
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  6. Andrea J. Wolf
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  7. Nandita Bose
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  8. Anissa S. H. Chan
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  9. Andrew S. Magee
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  10. Michael E. Danielson
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  11. Arthur Weiss
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  12. John P. Vasilakos
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  13. David M. Underhill
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Contributions

H.S.G. and D.M.U. designed the study; H.S.G., C.N.R., C.A.B., J.M., A.J.W., N.B., A.S.H.C. and D.M.U. performed the experiments; A.S.M., M.E.D. and J.P.V. purified, characterized and provided the β-glucans; T.R.K. and A.W. provided knockout mice and an antibody; T.R.K., A.W. and J.P.V. gave technical support and conceptual advice; H.S.G. and D.M.U. wrote the paper.

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Correspondence toDavid M. Underhill.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-33 with legends, additional references and full legends for Supplementary Movies 1-2. (PDF 7076 kb)

Supplementary Movie 1

This movie shows confocal microscopy imaging of the formation of a “phagocytic synapse” upon binding of a yeast particle to Dectin-1 on the surface of a macrophage - see Supplementary Information file for full legends. (MOV 3419 kb)

Supplementary Movie 2

This movie shows 3D modeling of a “phagocytic synapse” in a phagocytic cup formed at the surface of a macrophage upon detection of a yeast particle by Dectin-1 - see Supplementary Information file for full legends. (MOV 1396 kb)

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Goodridge, H., Reyes, C., Becker, C. et al. Activation of the innate immune receptor Dectin-1 upon formation of a ‘phagocytic synapse’.Nature 472, 471–475 (2011). https://doi.org/10.1038/nature10071

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Editorial Summary

How the innate immune system spots fungal pathogens

Invading microbes are detected and ingested by white blood cells known as phagocytes. To do this they must distinguish between soluble microbe-derived components, such as pieces of cell wall, and the particulate microbes themselves. A study of the action of Dectin-1, an innate immune receptor that detects invading fungal pathogens, shows that although the receptor binds to both soluble and particulate cell-wall β-glucans, its activation is restricted to sites of contact with fungal cell walls by the formation of 'phagocytic synapses'. The phagocytic synapse provides a mechanistic model for the specific detection of ligands associated with a microbial surface, as opposed to those released from microbes at a distance.