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

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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Figure 1: Particulate, but not soluble, β-glucans induce Dectin-1 signalling.
Figure 2: Immobilized β-glucans induce Dectin-1 signalling.
Figure 3: CD45 and CD148 regulate Dectin-1 signalling.
Figure 4: CD45 and CD148 phosphatases are excluded from the β-glucan particle contact site.

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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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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 to David 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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