RRAS2 shapes the TCR repertoire by setting the threshold for negative selection
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- dc.contributor.author Martínez-Riaño, Ana
- dc.contributor.author Bovolenta, Elena R.
- dc.contributor.author Boccasavia, Viola L.
- dc.contributor.author Ponomarenko, Julia
- dc.contributor.author Abia, David
- dc.contributor.author Oeste, Clara L.
- dc.contributor.author Fresno, Manuel
- dc.contributor.author van Santen, Hisse M.
- dc.contributor.author Alarcon, Balbino
- dc.date.accessioned 2022-05-16T10:57:01Z
- dc.date.available 2022-05-16T10:57:01Z
- dc.date.issued 2019
- dc.description.abstract Signal strength controls the outcome of αβ T cell selection in the thymus, resulting in death if the affinity of the rearranged TCR is below the threshold for positive selection, or if the affinity of the TCR is above the threshold for negative selection. Here we show that deletion of the GTPase RRAS2 results in exacerbated negative selection and above-normal expression of positive selection markers. Furthermore, Rras2-/- mice are resistant to autoimmunity both in a model of inflammatory bowel disease (IBD) and in a model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). We show that MOG-specific T cells in Rras2-/- mice have reduced affinity for MOG/I-Ab tetramers, suggesting that enhanced negative selection leads to selection of TCRs with lower affinity for the self-MOG peptide. An analysis of the TCR repertoire shows alterations that mostly affect the TCRα variable (TRAV) locus with specific VJ combinations and CDR3α sequences that are absent in Rras2-/- mice, suggesting their involvement in autoimmunity.
- dc.description.sponsorship This work was funded by grants from Comisión Interministerial de Ciencia y Tecnología (SAF2016-76394-R to B. Alarcon), the “Comunidad de Madrid” (S2017/BMD-3671 to M. Fresno and B. Alarcon), and the European Research Council (ERC 2013-Advanced Grant 334763 “NOVARIPP” to B. Alarcon). The Centre for Genomic Regulation acknowledges support of the Spanish Ministry of Economy and Competitiveness, “Centro de Excelencia Severo Ochoa,” the Centres de Recerca de Catalunya Program/Generalitat de Catalunya, and the Centro de Biología Molecular Severo Ochoa to the Fundación Ramón Areces
- dc.format.mimetype application/pdf
- dc.identifier.citation Martínez-Riaño A, Bovolenta ER, Boccasavia VL, Ponomarenko J, Abia D, Oeste CL et al. RRAS2 shapes the TCR repertoire by setting the threshold for negative selection. J Exp Med. 2019 Oct 7;216(10):2427-2447. DOI:10.1084/jem.20181959
- dc.identifier.doi http://dx.doi.org/10.1084/jem.20181959
- dc.identifier.issn 1540-9538
- dc.identifier.uri http://hdl.handle.net/10230/53093
- dc.language.iso eng
- dc.publisher Rockefeller University Press
- dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/334763
- dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-76394-R
- dc.relation.projectID https://creativecommons.org/licenses/by-nc-sa/4.0/
- dc.rights © 2019 Ana Martínez-Riaño et al. This article is distributed under the terms of a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/)
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.subject.other Genètica
- dc.title RRAS2 shapes the TCR repertoire by setting the threshold for negative selection
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion