{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:26:00Z","timestamp":1781105160907,"version":"3.54.1"},"reference-count":92,"publisher":"National Academy of Sciences","issue":"8","license":[{"start":{"date-parts":[[2019,8,6]],"date-time":"2019-08-06T00:00:00Z","timestamp":1565049600000},"content-version":"vor","delay-in-days":181,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R21 A1097337"],"award-info":[{"award-number":["R21 A1097337"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["R01 CA178844"],"award-info":[{"award-number":["R01 CA178844"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["T32 AI07425"],"award-info":[{"award-number":["T32 AI07425"]}],"id":[{"id":"10.13039\/100000060","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":[[2019,2,19]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>Provision of sufficient activating signals can drive self-tolerant T cells to cross-react on self-peptide-MHC in a breakdown of tolerance. This approach has been applied in the development of heteroclitic peptide vaccines, which retain sufficient similarity to self to allow reactivation of effector cells on unaltered self-epitopes but require detailed knowledge about the behavior of individual altered self-peptide antigens. We designed altered-self MHC mutant antigen-presenting molecules to drive CTL capable of cross-reacting on self-peptide-MHC and demonstrate the breaking of self-tolerance to defined and undefined self-antigens. These findings bear particular importance in the field of cancer immunotherapy in which breaking tolerance to weakly antigenic cancer-associated antigens is fundamental to vaccination strategies.<\/jats:p>","DOI":"10.1073\/pnas.1807465116","type":"journal-article","created":{"date-parts":[[2019,4,1]],"date-time":"2019-04-01T15:29:15Z","timestamp":1554132555000},"page":"3136-3145","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":5,"title":["Breaking tolerance with engineered class I antigen-presenting molecules"],"prefix":"10.1073","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2772-2965","authenticated-orcid":false,"given":"Christopher A.","family":"Parks","sequence":"first","affiliation":[{"name":"Department of Immunology, Mayo Clinic, Rochester, MN 55905;"},{"name":"Immunology PhD Program, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN 55905;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalli R.","family":"Henning","sequence":"additional","affiliation":[{"name":"Department of Immunology, Mayo Clinic, Rochester, MN 55905;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin D.","family":"Pavelko","sequence":"additional","affiliation":[{"name":"Department of Immunology, Mayo Clinic, Rochester, MN 55905;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Hansen","sequence":"additional","affiliation":[{"name":"Department of Immunology, Mayo Clinic, Rochester, MN 55905;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia P.","family":"Van Keulen","sequence":"additional","affiliation":[{"name":"Department of Immunology, Mayo Clinic, Rochester, MN 55905;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan K.","family":"Reed","sequence":"additional","affiliation":[{"name":"Department of Immunology, Mayo Clinic, Rochester, MN 55905;"},{"name":"Immunology PhD Program, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN 55905;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer D.","family":"Stone","sequence":"additional","affiliation":[{"name":"AbbVie Inc., North Chicago, IL 60064;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam G.","family":"Schrum","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212;"},{"name":"Department of Surgery, University of Missouri School of Medicine, Columbia, MO 65212;"},{"name":"Department of Bioengineering, University of Missouri, Columbia, MO 65212;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Gil","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65212;"},{"name":"Department of Surgery, University of Missouri School of Medicine, Columbia, MO 65212;"},{"name":"Department of Bioengineering, University of Missouri, Columbia, MO 65212;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Kranz","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Illinois, Urbana, IL 61801;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Bordner","sequence":"additional","affiliation":[{"name":"Sutter Health Design and Innovation, San Carlos, CA 94070;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Barry","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Infectious Diseases, Mayo Clinic, Rochester, MN 55905"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larry R.","family":"Pease","sequence":"additional","affiliation":[{"name":"Department of Immunology, Mayo Clinic, Rochester, MN 55905;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2019,2,6]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.180.1.1"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2008.07.001"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501657"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2012.333"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12477"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa4971"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S92182"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neo.2015.02.006"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(87)90568-X"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3667"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2938"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/0167-5699(89)90307-1"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01146"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.11.002"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2657"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201242606"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2012.02.006"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2013.10.001"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0952-7915(96)80078-1"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.182.5.1609"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.25.14809"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.9.1553"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1500415"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2017.1338996"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.01.018"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.02.008"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1102-999"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0398-321"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar4060"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2015.11.004"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.279.5354.1166"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.26.021607.090421"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032414-112334"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2007.05.022"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/384134a0"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80080-1"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2006.08.045"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)82275-X"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni863"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20062056"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-014-1586-z"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2010.10.041"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.3390\/genes8020079"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2006.01.022"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5293.1707"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.2007.02045.x"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/248701a0"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830040802"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/269417a0"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/344065a0"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.2.756"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.158.3807.1484"},{"key":"e_1_3_3_53_2","doi-asserted-by":"crossref","first-page":"802","DOI":"10.4049\/jimmunol.160.2.802","article-title":"Degenerate recognition of alloantigenic peptides on a positive-selecting class I molecule","volume":"160","author":"Tallquist MD","year":"1998","unstructured":"MD Tallquist, AJ Weaver, LR Pease, Degenerate recognition of alloantigenic peptides on a positive-selecting class I molecule. J Immunol 160, 802\u2013809 (1998).","journal-title":"J Immunol"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1067\/msy.2000.107421"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.10.5188"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1000629"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2017.1319028"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-10-250993"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2017014175"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12026-012-8348-9"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf1490"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature22991"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature23003"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.iy.11.040193.002125"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/cgt.2012.69"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1517\/13543784.2015.971154"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.16.6186"},{"key":"e_1_3_3_68_2","doi-asserted-by":"crossref","first-page":"2419","DOI":"10.4049\/jimmunol.155.5.2419","article-title":"Alloreactive 2C T cells recognize a self peptide in the context of the mutant Kbm3 molecule","volume":"155","author":"Tallquist MD","year":"1995","unstructured":"MD Tallquist, LR Pease, Alloreactive 2C T cells recognize a self peptide in the context of the mutant Kbm3 molecule. J Immunol 155, 2419\u20132426 (1995).","journal-title":"J Immunol"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.184.3.1017"},{"key":"e_1_3_3_70_2","doi-asserted-by":"crossref","first-page":"3445","DOI":"10.4049\/jimmunol.152.7.3445","article-title":"Recognition of a single amino acid change on the surface of a major transplantation antigen is in the context of self peptide","volume":"152","author":"Pullen JK","year":"1994","unstructured":"JK Pullen, MD Tallquist, RW Melvold, LR Pease, Recognition of a single amino acid change on the surface of a major transplantation antigen is in the context of self peptide. J Immunol 152, 3445\u20133452 (1994).","journal-title":"J Immunol"},{"key":"e_1_3_3_71_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.7.2794"},{"key":"e_1_3_3_72_2","doi-asserted-by":"crossref","first-page":"3981","DOI":"10.4049\/jimmunol.151.8.3981","article-title":"A conservative mutation in a class I MHC molecule outside the peptide binding groove stimulates responses to self peptides","volume":"151","author":"Grandea AG","year":"1993","unstructured":"3rd AG Grandea, MJ Bevan, A conservative mutation in a class I MHC molecule outside the peptide binding groove stimulates responses to self peptides. J Immunol 151, 3981\u20133987 (1993).","journal-title":"J Immunol"},{"key":"e_1_3_3_73_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0041-7"},{"key":"e_1_3_3_74_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.20185"},{"key":"e_1_3_3_75_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.540150503"},{"key":"e_1_3_3_76_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/28.1.235"},{"key":"e_1_3_3_77_2","doi-asserted-by":"publisher","DOI":"10.1002\/dvg.20335"},{"key":"e_1_3_3_78_2","unstructured":"; National Research Council Guide for the Care and Use of Laboratory Animals (National Academies Press Washington DC) 8th Ed. (2011)."},{"key":"e_1_3_3_79_2","first-page":"202","volume-title":"The Immune System","author":"K\u00f6hler G","year":"1981","unstructured":"G K\u00f6hler, KF Lindahl, C Heusser, Characterization of a monoclonal anti-H-2Kb antibody. The Immune System (Karger Publishers, Basel) Vol 2, 202\u2013208 (1981)."},{"key":"e_1_3_3_80_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.79.15.4737"},{"key":"e_1_3_3_81_2","doi-asserted-by":"publisher","DOI":"10.1038\/292547a0"},{"key":"e_1_3_3_82_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01561661"},{"key":"e_1_3_3_83_2","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-198209000-00001"},{"key":"e_1_3_3_84_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(78)90254-4"},{"key":"e_1_3_3_85_2","doi-asserted-by":"crossref","first-page":"3375","DOI":"10.4049\/jimmunol.150.8.3375","article-title":"Amino acid changes in the peptide binding site have structural consequences at the surface of class I glycoproteins","volume":"150","author":"Pease LR","year":"1993","unstructured":"LR Pease, , Amino acid changes in the peptide binding site have structural consequences at the surface of class I glycoproteins. J Immunol 150, 3375\u20133381 (1993).","journal-title":"J Immunol"},{"key":"e_1_3_3_86_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.12.5101"},{"key":"e_1_3_3_87_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00375866"},{"key":"e_1_3_3_88_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00720-16"},{"key":"e_1_3_3_89_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2004.15.1125"},{"key":"e_1_3_3_90_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2017.10.005"},{"key":"e_1_3_3_91_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0797-808"},{"key":"e_1_3_3_92_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2013.52"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.1807465116","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1807465116","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T03:39:19Z","timestamp":1694749159000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1807465116"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,6]]},"references-count":92,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2019,2,19]]}},"alternative-id":["10.1073\/pnas.1807465116"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1807465116","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,6]]},"assertion":[{"value":"2019-02-06","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}