Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters










Database
Language
Publication year range
1.
Blood ; 137(7): 923-928, 2021 02 18.
Article in English | MEDLINE | ID: mdl-33025005

ABSTRACT

In hematopoietic cell transplantation (HCT), permissive HLA-DPB1 mismatches between patients and their unrelated donors are associated with improved outcomes compared with nonpermissive mismatches, but the underlying mechanism is incompletely understood. Here, we used mass spectrometry, T-cell receptor-ß (TCRß) deep sequencing, and cellular in vitro models of alloreactivity to interrogate the HLA-DP immunopeptidome and its role in alloreactive T-cell responses. We find that permissive HLA-DPB1 mismatches display significantly higher peptide repertoire overlaps compared with their nonpermissive counterparts, resulting in lower frequency and diversity of alloreactive TCRß clonotypes in healthy individuals and transplanted patients. Permissiveness can be reversed by the absence of the peptide editor HLA-DM or the presence of its antagonist, HLA-DO, through significant broadening of the peptide repertoire. Our data establish the degree of immunopeptidome divergence between donor and recipient as the mechanistic basis for the clinically relevant permissive HLA-DPB1 mismatches in HCT and show that permissiveness is dependent on HLA-DM-mediated peptide editing. Its key role for harnessing T-cell alloreactivity to HLA-DP highlights HLA-DM as a potential novel target for cellular and immunotherapy of leukemia.


Subject(s)
Epitopes/immunology , HLA-D Antigens/immunology , HLA-DP beta-Chains/immunology , Histocompatibility/immunology , Peptides/immunology , Receptors, Antigen, T-Cell, alpha-beta/immunology , Allografts , Antigens, Differentiation, B-Lymphocyte/metabolism , CD4-Positive T-Lymphocytes/immunology , Cells, Cultured , Endosomes/metabolism , Epitopes/metabolism , Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor , Gene Rearrangement, beta-Chain T-Cell Antigen Receptor , HeLa Cells , Hematopoietic Stem Cell Transplantation , High-Throughput Nucleotide Sequencing , Histocompatibility/genetics , Histocompatibility Antigens Class II/metabolism , Humans , Mass Spectrometry , Molecular Chaperones , Peptides/metabolism , Receptors, Antigen, T-Cell, alpha-beta/genetics , Unrelated Donors
SELECTION OF CITATIONS
SEARCH DETAIL
...