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Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane

Abstract

Central to the initiation of immune responses is recognition of peptide antigen by T lymphocytes. The cell biology of dendritic cells makes them ideally suited for the essential process of antigen presentation1. Their life cycle includes several stages characterized by distinct functions and mechanisms of regulation2. Immature dendritic cells synthesize large amounts of major histocompatibility complex class II molecules (MHC II), but the αβ-dimers are targeted to late endosomes and lysosomes (often referred to as MHC class II compartments) where they reside unproductively with internalized antigens. After exposure to microbial products or inflammatory mediators, endocytosis is downregulated, the expression of co-stimulatory molecules is enhanced, and newly formed immunogenic MHC II–peptide complexes are transported to the cell surface3,4,5,6,7,8,9,10. That these MHC II molecules reach the surface is surprising, as the lysosomes comprise the terminal degradative compartment of the endocytic pathway from which exogenous components generally cannot be recovered intact11. Here we have visualized this pathway in live dendritic cells by video microscopy, using cells expressing MHC II tagged with green fluorescent protein (GFP). We show that on stimulation, dendritic cells generate tubules from lysosomal compartments that go on to fuse directly with the plasma membrane.

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Figure 1: MHC II-GFP expressed by dendritic cells exhibit properties characteristic of endogenous MHC II.
Figure 2: Export of MHC II-GFP molecules from lysosomes to the cell periphery occurs in tubular-vesicular structures in live dendritic cells imaged by confocal microscopy.
Figure 3: MHC II-GFP tubules originate from lysosomal/late endosomal compartments.
Figure 4: Combined TIR-FM/EPI microscopy demonstrates fusion of lysosome-derived MHC II-GFP structures with the plasma membrane.

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Acknowledgements

We thank members of the Mellman/Warren laboratory for general support and advice, in particular J. Seemann and L. Pelletier. We also thank J. Kagan, A. Neild and C. Roy for confocal microscopy assistance, L. Zheng and A. Bothwell for help with the retroviral system, and T. Hughes for providing the EGFP complementary DNA. We thank O. Bloom, J. Unternaehrer and J. Chow for critical reading of the manuscript, and Olympus for providing the TIR-FM microscope. We also thank the Ludwig Institute for Cancer Research and the NIH for their support of our work.

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Correspondence to Ira Mellman.

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Chow, A., Toomre, D., Garrett, W. et al. Dendritic cell maturation triggers retrograde MHC class II transport from lysosomes to the plasma membrane. Nature 418, 988–994 (2002). https://doi.org/10.1038/nature01006

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