Please use this identifier to cite or link to this item: https://hdl.handle.net/11147/13297
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dc.contributor.authorLo, Wan-Lin-
dc.contributor.authorKuhlmann, Miriam-
dc.contributor.authorRizzuto, Gabrielle-
dc.contributor.authorEkiz, H. Atakan-
dc.contributor.authorKolawole, Elizabeth M.-
dc.contributor.authorRevelo, Monica P.-
dc.contributor.authorAndargachew, Rakieb-
dc.date.accessioned2023-04-19T12:36:42Z-
dc.date.available2023-04-19T12:36:42Z-
dc.date.issued2023-
dc.identifier.issn1529-2908-
dc.identifier.issn1529-2916-
dc.identifier.urihttps://doi.org/10.1038/s41590-023-01444-x-
dc.identifier.urihttps://hdl.handle.net/11147/13297-
dc.description.abstractMature T cells must discriminate between brief interactions with self-peptides and prolonged binding to agonists. The kinetic proofreading model posits that certain T-cell antigen receptor signaling nodes serve as molecular timers to facilitate such discrimination. However, the physiological significance of this regulatory mechanism and the pathological consequences of disrupting it are unknown. Here we report that accelerating the normally slow phosphorylation of the linker for activation of T cells (LAT) residue Y136 by introducing an adjacent Gly135Asp alteration (LAT(G135D)) disrupts ligand discrimination in vivo. The enhanced self-reactivity of LAT(G135D) T cells triggers excessive thymic negative selection and promotes T-cell anergy. During Listeria infection, LAT(G135D) T cells expand more than wild-type counterparts in response to very weak stimuli but display an imbalance between effector and memory responses. Moreover, despite their enhanced engagement of central and peripheral tolerance mechanisms, mice bearing LAT(G135D) show features associated with autoimmunity and immunopathology. Our data reveal the importance of kinetic proofreading in balancing tolerance and immunity. Lo and colleagues provide evidence for the TCR kinetic proofreading model by LAT Gly135Asp alteration to reveal functional consequences of altered kinetics in TCR activation in thymic selection and mature T-cell responses.en_US
dc.description.sponsorshipWe thank A. Roque (University of California, San Francisco) and P. Noel (University of Utah) for animal husbandry; the University of California, San Francisco Parnassus Flow Cytometry Core and University of Utah Flow Cytometry Core for maintaining the BD FACSAria II; the National Institutes of Health Tetramer Core Facility for providing peptide-loaded tetramers; O. Stepanek (Czech Academy of Sciences), E. Huseby (University of Massachusetts Chan Medical School), G. Morris (University of California, San Diego), D. Tantin and M. Bettini (University of Utah), P. Allen (Washington University in St. Louis), P. Ebert (Adaptive Biotechnologies), B. Au-Yeung (Emory University) and the laboratory of B.D.E. (University of Utah) for critical feedback and discussion of the paper. The work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) K22 Career Transition Award AI143960 (to W.-L.L.), University of Utah School of Medicine Department of Pathology start-up funds and Career Development funds (to W.-L.L.), the Research Incentive Seed Grant award (W.-L.L.), NIAID Clinical Investigator Award K08 AI137209 (to G.R.), Memorial Sloan Kettering Cancer Center Human Oncology and Pathogenesis Program start-up funds (to G.R.), TUEBITAK-2232b 121C115 (to H.A.E.), the Cancer Research Institute Lloyd J. Old STAR award (to A.M.), the Parker Institute for Cancer Immunotherapy (to A.M.), the Innovative Genomics Institute (to A.M.), NIAID R01 AI147641 and R01 AI167422 (to B.D.E.), European Research Council Consolidator Grant ToCCaTa (to D.Z.), German Research Foundation SFB1054 and SFB1371 (D.Z.), the Howard Hughes Medical Institute (to A.W.) and NIAID P01 AI091580 (to A.W.).en_US
dc.language.isoenen_US
dc.publisherNature Portfolioen_US
dc.relation.ispartofNature Immunologyen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectT-Cellen_US
dc.subjectLAT proteinen_US
dc.subjectLymphocyte antigen receptoren_US
dc.subjectAmino acid substitutionen_US
dc.subjectPhosphoproteinsen_US
dc.titleA Single-Amino Acid Substitution in the Adaptor Lat Accelerates Tcr Proofreading Kinetics and Alters T-Cell Selection, Maintenance and Functionen_US
dc.typeArticleen_US
dc.authorid0000-0001-7718-6841-
dc.institutionauthorEkiz, H. Atakan-
dc.departmentİzmir Institute of Technology. Molecular Biology and Geneticsen_US
dc.identifier.volume24en_US
dc.identifier.issue4en_US
dc.identifier.startpage676en_US
dc.identifier.endpage689en_US
dc.identifier.wosWOS:000948715400001en_US
dc.identifier.scopus2-s2.0-85149913210en_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.identifier.doi10.1038/s41590-023-01444-x-
dc.identifier.pmid36914891en_US
dc.authorscopusid35072868000-
dc.authorscopusid57965197800-
dc.authorscopusid57204446834-
dc.authorscopusid36150568800-
dc.authorscopusid55893058800-
dc.authorscopusid6602242359-
dc.authorscopusid36655476900-
dc.identifier.wosqualityQ1-
dc.identifier.scopusqualityQ1-
item.fulltextNo Fulltext-
item.openairetypeArticle-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.languageiso639-1en-
item.cerifentitytypePublications-
item.grantfulltextnone-
crisitem.author.dept04.03. Department of Molecular Biology and Genetics-
Appears in Collections:Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
PubMed İndeksli Yayınlar Koleksiyonu / PubMed Indexed Publications Collection
Scopus İndeksli Yayınlar Koleksiyonu / Scopus Indexed Publications Collection
WoS İndeksli Yayınlar Koleksiyonu / WoS Indexed Publications Collection
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