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Surface expression of MHC class II in dendritic cells is controlled by regulated ubiquitination


Dendritic cells have a unique function in the immune response owing to their ability to stimulate immunologically naive T lymphocytes1. In response to microbial and inflammatory stimuli, dendritic cells enhance their capacity for antigen presentation by a process of terminal differentiation, termed maturation2,3. The conversion of immature to mature dendritic cells is accompanied by a marked cellular reorganization, including the redistribution of major histocompatibility complex class II molecules (MHC II) from late endosomal and lysosomal compartments to the plasma membrane4,5,6,7 and the downregulation of some forms of endocytosis, which has been thought to slow the clearance of MHC II from the surface8,9,10,11. The relative extent to which these or other mechanisms contribute to the regulation of surface MHC II remains unclear, however. Here we find that the MHC II β-chain cytoplasmic tail is ubiquitinated in mouse immature dendritic cells. Although only partly required for the sequestration of MHC II in multivesicular bodies, this modification is essential for endocytosis. Notably, ubiquitination of MHC II ceased upon maturation, resulting in the accumulation of MHC II at the cell surface. Dendritic cells thus exhibit a unique ability to regulate MHC II surface expression by selectively controlling MHC II ubiquitination.

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Figure 1: MHC class II molecules are ubiquitinated in dendritic cells.
Figure 2: Differential localization and endocytosis of wild-type MHC II versus the ubiquitin-deficient MHC IIβ(K>R) mutant.
Figure 3: Lysosomal degradation and Ii chain association of ubiquitinated and non-ubiquitinated MHC II in BMDCs.
Figure 4: Loss of MHC II ubiquitination in mature dendritic cells and its role in regulating endocytosis.

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We thank members of the Mellarren laboratory group for advice and support. J.-S.S. is a Fellow of the Jane Coffin Childs Foundation. I.M. is an Affiliate Member of the Ludwig Institute for Cancer Research. This work was supported by the NIH and by the Ludwig Institute for Cancer Research.

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Correspondence to Ira Mellman.

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Shin, JS., Ebersold, M., Pypaert, M. et al. Surface expression of MHC class II in dendritic cells is controlled by regulated ubiquitination. Nature 444, 115–118 (2006).

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