JCB logo
Avanti Polar Lipids, Inc.
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 1003K)
Right arrow PPT slides of all figures
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JCB
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Faigle, W.
Right arrow Articles by Amigorena, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Faigle, W.
Right arrow Articles by Amigorena, S.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

© The Rockefeller University Press, 0021-9525/1998//1121 $5.00
The Journal of Cell Biology, Volume 141, Number 5, , 1998 1121-1134

Articles

Deficient Peptide Loading and MHC Class II Endosomal Sorting in a Human Genetic Immunodeficiency Disease: the Chediak-Higashi Syndrome



Wolfgang Faigle*, Graça Raposo{ddagger}, Daniele Tenza{ddagger}, Valérie Pinet§, Anne B. Vogt||, Harald Kropshofer||, Alain Fischer, Geneviève de Saint-Basile, and Sebastian Amigorena*

* CJF 95-01 INSERM and {ddagger} UMR144 CNRS, Institut Curie, 75005 Paris, France; § INSERM U475, Hôpital St. Eloi, 34295 Montpellier, France; || Department of Molecular Immunology, DKFZ, 69120 Heidelberg, Germany; and INSERM U429, Hôpital Necker Enfants Malades, 75015 Paris, France

The Chediak-Higashi syndrome (CHS) is a human recessive autosomal disease caused by mutations in a single gene encoding a protein of unknown function, called lysosomal-trafficking regulator. All cells in CHS patients bear enlarged lysosomes. In addition, T- and natural killer cell cytotoxicity is defective in these patients, causing severe immunodeficiencies. We have analyzed major histocompatibility complex class II functions and intracellular transport in Epstein Barr Virus–transformed B cells from CHS patients. Peptide loading onto major histocompatibility complex class II molecules and antigen presentation are strongly delayed these cells. A detailed electron microscopy analysis of endocytic compartments revealed that only lysosomal multilaminar compartments are enlarged (reaching 1–2 µm), whereas late multivesicular endosomes have normal size and morphology. In contrast to giant multilaminar compartments that bear most of the usual lysosomal markers in these cells (HLA-DR, HLA-DM, Lamp-1, CD63, etc.), multivesicular late endosomes displayed reduced levels of all these molecules, suggesting a defect in transport from the trans-Golgi network and/or early endosomes into late multivesicular endosomes. Further insight into a possible mechanism of this transport defect came from immunolocalizing the lysosomal trafficking regulator protein, as antibodies directed to a peptide from its COOH terminal domain decorated punctated structures partially aligned along microtubules. These results suggest that the product of the Lyst gene is required for sorting endosomal resident proteins into late multivesicular endosomes by a mechanism involving microtubules.

Abbreviations used in this paper: BSA-G, colloidal gold–coupled bovine serum albumin; CD-MPR, cation-dependent mannose-6-phosphate receptor; CHS, Chediak-Higashi syndrome; DAMP, N-3-(2,4-dinitroanilino)- 3-amino-N-methyldipropylamine; EBV-B cell, Epstein Barr virus–transformed B cell; HA, hemagglutinin; Ii, invariant chain; LYST, lysosomal trafficking regulator; MHC, major histocompatibility complex; MIIC, MHC class II compartment; mIg, membrane immunoglobulins; PI3K, phosphatidylinositol-3 kinase.

W. Faigle is supported by the INSERM. This work was supported by grants from the Curie Institute, the Institut National de la Santé et Recherche Medicale, the Centre National de la Recherche Scientifique, Vaincre les Maladies Lysosomales, Ligue Nationale Contre le Cancer, and Association pour la Recherche Contre le Cancer.

W. Faigle and G. Raposo contributed equally to this work.

Address all correspondence to S. Amigorena, CJF 95-01 INSERM, Institut CURIE, Section Recherche, 12 Rue Lhomond, 75005, Paris, France. Tel.: 33-1-4234-6389; Fax: 33-1-4234-6382; E-mail: s.amigorena{at}curie.fr


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents