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The Journal of Immunology, 2002, 169: 5052-5060.
Copyright © 2002 by The American Association of Immunologists

HLA-DR4 Molecules in Neuroendocrine Epithelial Cells Associate to a Heterogeneous Repertoire of Cytoplasmic and Surface Self Peptides1

Aura Muntasell*,{dagger}, Montserrat Carrascal{ddagger}, Laurence Serradell*, Peter van Veelen§, Frank Verreck§, Frits Koning§, Graça Raposo, Joaquín Abián{ddagger} and Dolores Jaraquemada2,*,{dagger}

* Immunology Unit and {dagger} Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Barcelona, Spain; {ddagger} Structural and Biological Mass Spectrometry Unit, Department of Medical Bioanalysis, Institut d’Investigació Biomèdica de Barcelona-Consejo Superior de Investigaciones Científicas, Institut d’Investigacios Biomèdiques August Pi i Sunyer, Barcelona, Spain; § Immunohaematology and Bloodbank Department, Leiden University Medical Center, Leiden, The Netherlands; and Unité Mixte de Recherche, 144 Centre National de la Recherche Scientifique, Compartimentation et Dynamique Cellulaire, Institute Curie, Paris, France

Expression of MHC class II genes by epithelial cells is induced in inflammatory conditions such as autoimmunity and organ transplantation. Class II ligands generated by the epithelial cell processing mechanisms are unknown, although some unique epitopes have been described in epithelial cells that B cells could not generate. Epithelial cells are the targets of autoreactive T cell responses in autoimmune diseases and of transplant rejection processes, which may involve recognition of cell type-specific epitopes. In the present report, we have compared the DR4-associated repertoire and the intracellular distribution of class II, invariant chain (Ii), and DM molecules between a human DR4-, Ii-, and DM-transfected rat neuroendocrine epithelial cell line and a homozygous DR4 (DRB1*0401) lymphoblastoid B cell line, by mass spectrometry sequencing techniques, and immunoelectron microscopy. The epithelial cells chosen for transfection, RINm5F, are rat insular cells widely used for human studies of autoimmune diabetes. The results revealed a remarkably heterogeneous pool of self protein-derived peptides from the cell surface and various intracellular compartments, including the cytosol and secretory vesicles in epithelial cells, compared with a very restricted homogeneous repertoire in lymphoblastoid B cell lines, where few epitopes from surface molecules were predominant. The generation of distinct DR4-associated peptide repertoires in these two cell types could be due to the effect of several factors including differences in subcellular location of Ii and DM molecules, differential DO expression, and cell type-specific mechanisms of class II ligand generation. This is specially relevant to processes involving epithelial T cell interactions such as organ-specific autoimmunity and transplant rejection.




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