2026-04-27T20:01:10Zhttps://uvadoc.uva.es/oai/request

oai:uvadoc.uva.es:10324/643002024-12-16T09:05:18Zcom_10324_1134com_10324_931com_10324_894col_10324_1213

Fu, Guo Casas Requena, Javier Rigaud, Stephanie Rybakin, Vasily Lambolez, Florence Brzostek, Joanna Hoerter, John A. H. Paster, Wolfgang Acuto, Oreste Cheroutre, Hilde Sauer, Karsten Gascoigne, Nicholas R. J. 2024-01-08T14:31:39Z 2024-01-08T14:31:39Z 2013 Nature 504:441–445. https://doi.org/10.1038/nature12718 0028-0836 https://uvadoc.uva.es/handle/10324/64300 10.1038/nature12718 441 7480 445 Nature 504 1476-4687 This 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. eng info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/4.0/ Atribución 4.0 Internacional Themis sets the signal threshold for positive and negative selection in T-cell development info:eu-repo/semantics/article