Themis sets the signal threshold for positive and negative selection in T-cell development

Autor: Vasily Rybakin, Wolfgang Paster, Karsten Sauer, Oreste Acuto, Florence Lambolez, Hilde Cheroutre, Joanna Brzostek, Javier Casas, John A. H. Hoerter, Nicholas R. J. Gascoigne, Stephanie Rigaud, Guo Fu
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Zdroj: Nature
ISSN: 1476-4687
0028-0836
Popis: 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' precursors. 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 cells. Here we show that positive selection is enabled by the ability of the T-cell-specific protein Themis 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.
Databáze: OpenAIRE