HLA-DO is a negative modulator of HLA-DM-mediated MHC class II peptide loading

Class II molecules of the major histocompatibility complex become loaded with antigenic peptides after dissociation of invariant chainderived peptides (CLIP) from the peptide-binding groove. The human leukocyte antigen (HLA)-DM is a prerequisite for this process, which takes place in specialised int...

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Bibliographic Details
Published in:	Current biology Vol. 7; no. 12; p. 950
Main Authors:	van Ham, S M, Tjin, E P, Lillemeier, B F, Grüneberg, U, van Meijgaarden, K E, Pastoors, L, Verwoerd, D, Tulp, A, Canas, B, Rahman, D, Ottenhoff, T H, Pappin, D J, Trowsdale, J, Neefjes, J
Format:	Journal Article
Language:	English
Published:	England 01.12.1997
Subjects:	Amino Acid Sequence Antigen Presentation Antigens, Differentiation, B-Lymphocyte - metabolism Cell Line Histocompatibility Antigens Class II - metabolism HLA-D Antigens - genetics HLA-D Antigens - metabolism HLA-DR3 Antigen - metabolism Humans Molecular Sequence Data Recombinant Fusion Proteins - genetics Recombinant Fusion Proteins - metabolism Transfection
ISSN:	0960-9822
Online Access:	Get more information
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Summary:	Class II molecules of the major histocompatibility complex become loaded with antigenic peptides after dissociation of invariant chainderived peptides (CLIP) from the peptide-binding groove. The human leukocyte antigen (HLA)-DM is a prerequisite for this process, which takes place in specialised intracellular compartments. HLA-DM catalyses the peptide-exchange process, simultaneously functioning as a peptide 'editor', favouring the presentation of stably binding peptides. Recently, HLA-DO, an unconventional class II molecule, has been found associated with HLA-DM in B cells, yet its function has remained elusive. The function of the HLA-DO complex was investigated by expression of both chains of the HLA-DO heterodimer (either alone or fused to green fluorescent protein) in human Mel JuSo cells. Expression of HLA-DO resulted in greatly enhanced surface expression of CLIP via HLA-DR3, the conversion of class II complexes to the SDS-unstable phenotype and reduced antigen presentation to T-cell clones. Analysis of peptides eluted from HLA-DR3 demonstrated that CLIP was the major peptide bound to class II in the HLA-DO transfectants. Peptide exchange assays in vitro revealed that HLA-DO functions directly at the level of class II peptide loading by inhibiting the catalytic action of HLA-DM. HLA-DO is a negative modulator of HLA-DM. By stably associating with HLA-DM, the catalytic action of HLA-DM on class II peptide loading is inhibited. HLA-DO thus affects the peptide repertoire that is eventually presented to the immune system by MHC class II molecules.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-9822
DOI:	10.1016/S0960-9822(06)00414-3