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J Exp Med. 2019 Oct 7;216(10):2427-2447. doi: 10.1084/jem.20181959. Epub 2019 Jul 19.

RRAS2 shapes the TCR repertoire by setting the threshold for negative selection.

Author information

1
Departamento de Biología Celular e Inmunología, Centro Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain.
2
Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain.
3
Universitat Pompeu Fabra, Barcelona, Spain.
4
Servicio de Bioinformática, Centro Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain.
5
Departamento de Biología Celular e Inmunología, Centro Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain hvansanten@cbm.csic.es.
6
Departamento de Biología Celular e Inmunología, Centro Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain balarcon@cbm.csic.es.

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.

PMID:
31324740
DOI:
10.1084/jem.20181959

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