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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| Published in: | Current biology Vol. 7; no. 12; p. 950 |
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| Main Authors: | , , , , , , , , , , , , , |
| Format: | Journal Article |
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01.12.1997
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| ISSN: | 0960-9822 |
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| Abstract | 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. |
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| AbstractList | 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. 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.BACKGROUNDClass 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.RESULTSThe 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.CONCLUSIONSHLA-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. |
| Author | Verwoerd, D Canas, B Rahman, D Ottenhoff, T H van Ham, S M Tjin, E P Neefjes, J Pastoors, L Trowsdale, J Lillemeier, B F van Meijgaarden, K E Grüneberg, U Pappin, D J Tulp, A |
| Author_xml | – sequence: 1 givenname: S M surname: van Ham fullname: van Ham, S M email: vanham@nki.nl organization: Department of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX Amsterdam, The Netherlands. vanham@nki.nl – sequence: 2 givenname: E P surname: Tjin fullname: Tjin, E P – sequence: 3 givenname: B F surname: Lillemeier fullname: Lillemeier, B F – sequence: 4 givenname: U surname: Grüneberg fullname: Grüneberg, U – sequence: 5 givenname: K E surname: van Meijgaarden fullname: van Meijgaarden, K E – sequence: 6 givenname: L surname: Pastoors fullname: Pastoors, L – sequence: 7 givenname: D surname: Verwoerd fullname: Verwoerd, D – sequence: 8 givenname: A surname: Tulp fullname: Tulp, A – sequence: 9 givenname: B surname: Canas fullname: Canas, B – sequence: 10 givenname: D surname: Rahman fullname: Rahman, D – sequence: 11 givenname: T H surname: Ottenhoff fullname: Ottenhoff, T H – sequence: 12 givenname: D J surname: Pappin fullname: Pappin, D J – sequence: 13 givenname: J surname: Trowsdale fullname: Trowsdale, J – sequence: 14 givenname: J surname: Neefjes fullname: Neefjes, J |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/9382849$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | 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 |
| Title | HLA-DO is a negative modulator of HLA-DM-mediated MHC class II peptide loading |
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