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Toll-dependent selection of microbial antigens for presentation by dendritic cells

Nature volume 440, pages 808–812 (2006)Cite this article

Abstract

Dendritic cells constitutively sample the tissue microenvironment and phagocytose both microbial and host apoptotic cells1,2,3,4. This leads to the induction of immunity against invading pathogens or tolerance to peripheral self antigens, respectively5,6,7,8,9. The outcome of antigen presentation by dendritic cells depends on their activation status, such that Toll-like receptor (TLR)-induced dendritic cell activation makes them immunogenic, whereas steady-state presentation of self antigens leads to tolerance5,6,8,10. TLR-inducible expression of co-stimulatory signals is one of the mechanisms of self/non-self discrimination5,11. However, it is unclear whether or how the inducible expression of co-stimulatory signals would distinguish between self antigens and microbial antigens when both are encountered by dendritic cells during infection6,8. Here we describe a new mechanism of antigen selection in dendritic cells for presentation by major histocompatibility complex class II molecules (MHC II) that is based on the origin of the antigen. We show that the efficiency of presenting antigens from phagocytosed cargo is dependent on the presence of TLR ligands within the cargo. Furthermore, we show that the generation of peptide–MHC class II complexes is controlled by TLRs in a strictly phagosome-autonomous manner.

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Figure 1: Apoptotic cells phagocytosed into MHC-II + , LAMP-1 + compartments cause DC maturation only when accompanied by a TLR signal.
Figure 2: Antigens from apoptotic cells are not presented by MHC II unless they carry a TLR ligand.
Figure 3: MHC II presentation of phagocytosed particulate antigens is determined by the ability of cargo to engage TLRs.
Figure 4: TLR engagement by phagocytosed cargo controls phagosome-autonomous MHC II presentation.

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Acknowledgements

We are grateful to I. Mellman, M. Bevan, J. Monaco and R. Germain for reagents, and E. Kopp for the flagellin–OVA fusion construct. We thank P. Cresswell and A. Rudensky for reagents, suggestions and critical reading of the manuscript. We are indebted to I. Mellman, E.S. Trombetta, L. Delamarre and J. Kagan for discussions; M. Pypaert and C. Marks for electron microscopy; C. Chalouni and R. Montgomery for confocal microscopy; A. Hartley for 3D reconstructions; D. Amsen, A. Giodini, R. Teal, T. Horng, T. Potseleuva, C. Annicelli, S. Holley, R. Couture, D. Matosian, T. Taylor, G. Tokmoulina, J. Shanabrough, M. Blander and S.J. Blander for assistance and support. J.M.B. is supported by an Arthritis Investigator award. R.M. is supported by the Howard Hughes Medical Institute and the NIH.

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  1. J. Magarian Blander

    Present address: Center for Immunobiology, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York, 10029, USA

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  1. Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, 300 Cedar Street, Connecticut, 06520, New Haven, USA

    J. Magarian Blander & Ruslan Medzhitov

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Correspondence to Ruslan Medzhitov.

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Supplementary information

Supplementary Methods

This file contains additional details of the methods used in this study. (PDF 129 kb)

Supplementary Method Figure 1

The phagosomal pellet F10 consists of intact phagosomes that contain LAMP-2 and Rab-7. Following ultracentrifugation, an aliquot of the pellet F10 was diluted in RPMI medium and centrifuged onto alcian blue treated glass coverslips at 4000 rpm for 15 min. Phagosomes were fixed onto coverslips with 4% paraformaldehyde, quenched in glycine and stained. (PDF 609 kb)

Supplementary Figures

This file contains Supplementary Figures 1–14. (PDF 7770 kb)

Supplementary Movie 1.

A confocal three dimensional reconstructed image from Fig. 4e (top panels) is shown rotating at different angles. CD11c+ DC at 5 h post phagocytosis of both 4.5 µm HEL and 10 µm HEL/LPS conjugated microspheres. The C4H3 epitope (red) was detected around the phagosome containing the 10 µm microsphere by intracellular staining. I-Ak is shown in green and surface CTB in blue. (MOV 3761 kb)

Supplementary Movie 2.

A confocal three dimensional reconstructed image from Fig. 4e (bottom panels) shown rotating at different angles. CD11c+ DC at 5 h post phagocytosis of both 4.5 µm HEL/LPS and 10 µm HEL conjugated microspheres. Intracellular C4H3 epitope (red) was detected staining the phagosome containing the 4.5 µm microsphere. I-Ak is shown in green and surface CTB in blue. (MOV 1857 kb)

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Blander, J., Medzhitov, R. Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature 440, 808–812 (2006). https://doi.org/10.1038/nature04596

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