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PMID: 8947036 Published · ppublish English Journal Article

Editing of the HLA-DR-peptide repertoire by HLA-DM.

The EMBO journal ·Vol. 15 ·No. 22 ·1996-11-15 ·Pages 6144-54

Kropshofer H, Vogt AB, Moldenhauer G, Hammer J, Blum JS, Hämmerling GJ

Abstract

Antigenic peptide loading of classical major histocompatibility complex (MHC) class II molecules requires the exchange of the endogenous invariant chain fragment CLIP (class II associated Ii peptide) for peptides derived from antigenic proteins. This process is facilitated by the non-classical MHC class II molecule HLA-DM (DM) which catalyzes the removal of CLIP. Up to now it has been unclear whether DM releases self-peptides other than CLIP and thereby modifies the peptide repertoire presented to T cells. Here we report that DM can release a variety of peptides from HLA-DR molecules. DR molecules isolated from lymphoblastoid cell lines were found to carry a sizeable fraction of self-peptides that are sensitive to the action of DM. The structural basis for this DM sensitivity was elucidated by high-performance size exclusion chromatography and a novel mass spectrometry binding assay. The results demonstrate that the overall kinetic stability of a peptide bound to DR determines its sensitivity to removal by DM. We show that DM removes preferentially those peptides that contain at least one suboptimal side chain at one of their anchor positions or those that are shorter than 11 residues. These findings provide a rationale for the previously described ligand motifs and the minimal length requirements of naturally processed DR-associated self-peptides. Thus, in endosomal compartments, where peptide loading takes place, DM can function as a versatile peptide editor that selects for high-stability MHC class II-peptide complexes by kinetic proofreading before these complexes are presented to T cells.

MeSH Terms
Amino Acid Sequence Antigens, Differentiation, B-Lymphocyte/metabolism Blotting, Western HLA-D Antigens/immunology,metabolism,pharmacology HLA-DR Antigens/immunology,metabolism Histocompatibility Antigens Class II/metabolism Humans Kinetics Lysine/chemistry Major Histocompatibility Complex/immunology Mass Spectrometry Molecular Sequence Data Mutation/genetics Peptides/chemistry,metabolism Precipitin Tests Tumor Cells, Cultured
Chemicals
Antigens, Differentiation, B-Lymphocyte H2-M antigens HLA-D Antigens HLA-DM antigens HLA-DR Antigens Histocompatibility Antigens Class II Peptides invariant chain Lysine
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Kropshofer H
German Cancer Research Center, Department of Molecular Immunology, Heidelberg, Germany.
Vogt A B
Moldenhauer G
Hammer J
Blum J S
Hämmerling G J
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1996-11-15
Pages
6144-54
Language
English
Region
England
NLM ID
8208664
PMCID
PMC452435
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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