{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T03:36:23Z","timestamp":1784950583768,"version":"3.55.0"},"reference-count":28,"publisher":"National Academy of Sciences","issue":"49","license":[{"start":{"date-parts":[[2022,11,29]],"date-time":"2022-11-29T00:00:00Z","timestamp":1669680000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["KL 3292\/1-1"],"award-info":[{"award-number":["KL 3292\/1-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["NKB2008-4263"],"award-info":[{"award-number":["NKB2008-4263"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["UL2013-5989"],"award-info":[{"award-number":["UL2013-5989"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,12,6]]},"abstract":"<jats:p>\n                    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\u2013restricted CD4\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:sub>(142\u2013158)<\/jats:sub>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2214331119","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T17:14:31Z","timestamp":1669655671000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":29,"title":["Human T cells recognize HLA-DP\u2013bound peptides in two\u00a0orientations"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1364-0763","authenticated-orcid":false,"given":"Sebastian","family":"Klobuch","sequence":"first","affiliation":[{"name":"Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6097-6238","authenticated-orcid":false,"given":"Jia Jia","family":"Lim","sequence":"additional","affiliation":[{"name":"Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9670-4664","authenticated-orcid":false,"given":"Peter","family":"van Balen","sequence":"additional","affiliation":[{"name":"Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8960-7348","authenticated-orcid":false,"given":"Michel G. D.","family":"Kester","sequence":"additional","affiliation":[{"name":"Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"de Klerk","sequence":"additional","affiliation":[{"name":"Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnoud H.","family":"de Ru","sequence":"additional","affiliation":[{"name":"Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9761-3123","authenticated-orcid":false,"given":"Cilia R.","family":"Pothast","sequence":"additional","affiliation":[{"name":"Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9042-6459","authenticated-orcid":false,"given":"Inge","family":"Jedema","sequence":"additional","affiliation":[{"name":"Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4808-5296","authenticated-orcid":false,"given":"Jan W.","family":"Drijfhout","sequence":"additional","affiliation":[{"name":"Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2020-7522","authenticated-orcid":false,"given":"Jamie","family":"Rossjohn","sequence":"additional","affiliation":[{"name":"Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia"},{"name":"Institute of Infection and Immunity, Cardiff University, School of Medicine, Cardiff CF14 4XN, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6929-5001","authenticated-orcid":false,"given":"Hugh H.","family":"Reid","sequence":"additional","affiliation":[{"name":"Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter A.","family":"van Veelen","sequence":"additional","affiliation":[{"name":"Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. H. Frederik","family":"Falkenburg","sequence":"additional","affiliation":[{"name":"Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam H. M.","family":"Heemskerk","sequence":"additional","affiliation":[{"name":"Department of Hematology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,11,29]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST20210410"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032414-112334"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00172063"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1014708107"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2000192"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M112.024810"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0289-6"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts621"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13279"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1006"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.2.739"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1186\/1745-7580-4-6"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2014.06.020"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2012.07.008"},{"key":"e_1_3_4_15_2","first-page":"D783","article-title":"Allele frequency net database (AFND) 2020 update: Gold-standard data classification, open access genotype data and new query tools","volume":"48","author":"Gonzalez-Galarza F. F.","year":"2020","unstructured":"F. F. Gonzalez-Galarza , Allele frequency net database (AFND) 2020 update: Gold-standard data classification, open access genotype data and new query tools. 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