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Conformational Variation of Surface Class II MHC Proteins during Myeloid Dendritic Cell Differentiation Accompanies Structural Changes in Lysosomal MIIC¹

Ilaria Potolicchio^*,, Sriram Chitta, Xiaonan Xu^*, Dora Fonseca^*, Giovanna Crisi, Vaclav Horejsi^¶, Jack L. Strominger^||, Lawrence J. Stern, Graca Raposo and Laura Santambrogio^2,*

^* Department of Pathology Albert Einstein College of Medicine, New York, NY 10461; Institut Curie Centre National de la Recherche Scientifique, Unité Mixte de Recherche, Paris, France; Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655; Department of Pathology, Baystate Medical Center, Springfield, MA 01199; ^¶ Institute of Molecular Genetics, Academy of Sciences, Prague, Czech Republic; and ^|| Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138

Dendritic cells (DC), uniquely among APC, express an open/empty conformation of MHC class II (MHC-II) proteins (correctly folded molecules lacking bound peptides). Generation and trafficking of empty HLA-DR during DC differentiation are investigated here. HLA-DR did not fold as an empty molecule in the endoplasmic reticulum/trans-Golgi network, did not derived from MHC/Ii complexes trafficking to the cell surface, but was generated after invariant chain degradation within lysosomal-like MHC-II rich compartments (MIIC). In pre-DC, generated from monocytes cultured in the presence of GM-CSF, Lamp-1⁺MHC-II⁺ compartments are predominantly electron dense and, in these cells, empty MHC-II molecules accounts for as much as 20% of total surface HLA-DR. In immature DC, generated in presence of GM-CSF and IL-4, empty HLA-DR reside in multilamellar MIIC, but are scarcely observed at the cell surface. Thus, the morphology/composition of lysosomal MIIC at different DC maturational stages appear important for surface egression or intracellular retention of empty HLA-DR. Ag loading can be achieved for the fraction of empty HLA-DR present in the "peptide-receptive" form. Finally, in vivo, APC-expressing surface empty HLA-DR were found in T cell areas of secondary lymphoid organs.

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The JI 2005 175: 4827-4828. [Full Text]  

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