| Autor: |
Klobuch S; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Lim JJ; Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia., van Balen P; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Kester MGD; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., de Klerk W; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., de Ru AH; Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Pothast CR; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Jedema I; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Drijfhout JW; Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Rossjohn J; Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.; Institute of Infection and Immunity, Cardiff University, School of Medicine, Cardiff CF14 4XN, United Kingdom., Reid HH; Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia., van Veelen PA; Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Falkenburg JHF; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands., Heemskerk MHM; Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands. |
| Abstrakt: |
Human leukocyte antigen (HLA) molecules present small peptide antigens to T cells, thereby allowing them to recognize pathogen-infected and cancer cells. A central dogma over the last 50+ y is that peptide binding to HLA molecules is mediated by the docking of side chains of particular amino acids in the peptide into pockets in the HLA molecules in a conserved N- to C-terminal orientation. Whether peptides can be presented in a reversed C- to N-terminal orientation remains unclear. Here, we performed large-scale identification of peptides bound to HLA-DP molecules and observed that in addition to peptide binding in an N- to C-terminal orientation, in 9 out of 14 HLA-DP allotypes, reverse motifs are found, compatible with C- to N-terminal peptide binding. Moreover, we isolated high-avidity human cytomegalovirus (CMV)-specific HLA-DP-restricted CD4 + T cells from the memory repertoire of healthy donors and demonstrate that such T cells recognized CMV-derived peptides bound to HLA-DPB1*01:01 or *05:01 in a reverse C- to N-terminal manner. Finally, we obtained a high-resolution HLA-DPB1*01:01-CMVpp65 (142-158) peptide crystal structure, which is the molecular basis for C- to N-terminal peptide binding to HLA-DP. Our results point to unique features of HLA-DP molecules that substantially broaden the HLA class II bound peptide repertoire to combat pathogens and eliminate cancer cells. |
