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dc.contributor.authorFu, Guo
dc.contributor.authorCasas, Javier
dc.contributor.authorRigaud, Stephanie
dc.contributor.authorRybakin, Vasily
dc.contributor.authorLambolez, Florence
dc.contributor.authorBrzostek, Joanna
dc.contributor.authorHoerter, John A. H.
dc.contributor.authorPaster, Wolfgang
dc.contributor.authorAcuto, Oreste
dc.contributor.authorCheroutre, Hilde
dc.contributor.authorSauer, Karsten
dc.contributor.authorGascoigne, Nicholas R. J.
dc.date.accessioned2024-01-08T14:31:39Z
dc.date.available2024-01-08T14:31:39Z
dc.date.issued2013
dc.identifier.citationNature 504:441–445. https://doi.org/10.1038/nature12718es
dc.identifier.issn0028-0836es
dc.identifier.urihttps://uvadoc.uva.es/handle/10324/64300
dc.descriptionProducción Científicaes
dc.description.abstractThis work shows that the Themis protein has a critical role in positive and negative thymocyte selection by dampening responses to low-affinity ligands but without affecting responses to high-affinity ligands, thus enabling positive selection of weakly self-reactive thymocytes. Themis is a protein expressed in T cells. Mice lacking it have severely reduced numbers of single-positive thymocytes and peripheral T cells, although the mechanism by which Themis controls T-cell development or function remains obscure. Nicholas Gascoigne and colleagues show here that Themis has a crucial role in thymocyte selection by regulating the signalling threshold between positive and negative selection. It dampens responses to low-affinity ligands but does not affect responses to high-affinity ligands, thus enabling positive selection of weakly self-reactive thymocytes. Development of a self-tolerant T-cell receptor (TCR) repertoire with the potential to recognize the universe of infectious agents depends on proper regulation of TCR signalling. The repertoire is whittled down during T-cell development in the thymus by the ability of quasi-randomly generated TCRs to interact with self-peptides presented by major histocompatibility complex (MHC) proteins. Low-affinity TCR interactions with self-MHC proteins generate weak signals that initiate ‘positive selection’, causing maturation of CD4- or CD8αβ-expressing ‘single-positive’ thymocytes from CD4+CD8αβ+ ‘double-positive’ precursors1. These develop into mature naive T cells of the secondary lymphoid organs. TCR interaction with high-affinity agonist self-ligands results in ‘negative selection’ by activation-induced apoptosis or ‘agonist selection’ of functionally differentiated self-antigen-experienced T cells2,3. Here we show that positive selection is enabled by the ability of the T-cell-specific protein Themis4,5,6,7,8,9 to specifically attenuate TCR signal strength via SHP1 recruitment and activation in response to low- but not high-affinity TCR engagement. Themis acts as an analog-to-digital converter translating graded TCR affinity into clear-cut selection outcome. By dampening mild TCR signals Themis increases the affinity threshold for activation, enabling positive selection of T cells with a naive phenotype in response to low-affinity self-antigens.es
dc.format.mimetypeapplication/pdfes
dc.language.isoenges
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.titleThemis sets the signal threshold for positive and negative selection in T-cell developmentes
dc.typeinfo:eu-repo/semantics/articlees
dc.identifier.doi10.1038/nature12718es
dc.identifier.publicationfirstpage441es
dc.identifier.publicationissue7480es
dc.identifier.publicationlastpage445es
dc.identifier.publicationtitleNaturees
dc.identifier.publicationvolume504es
dc.peerreviewedSIes
dc.identifier.essn1476-4687es
dc.rightsAtribución 4.0 Internacional*
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersiones


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