RT info:eu-repo/semantics/article
T1 Themis sets the signal threshold for positive and negative selection in T-cell development
A1 Fu, Guo
A1 Casas, Javier
A1 Rigaud, Stephanie
A1 Rybakin, Vasily
A1 Lambolez, Florence
A1 Brzostek, Joanna
A1 Hoerter, John A. H.
A1 Paster, Wolfgang
A1 Acuto, Oreste
A1 Cheroutre, Hilde
A1 Sauer, Karsten
A1 Gascoigne, Nicholas R. J.
AB 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.
SN 0028-0836
YR 2013
FD 2013
LK https://uvadoc.uva.es/handle/10324/64300
UL https://uvadoc.uva.es/handle/10324/64300
LA eng
NO Nature 504:441–445. https://doi.org/10.1038/nature12718
NO Producción Científica
DS UVaDOC
RD 27-jun-2024