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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.

Original publication

DOI

10.1038/nature12718

Type

Journal article

Journal

Nature

Publication Date

19/12/2013

Volume

504

Pages

441 - 445

Keywords

Animals, Apoptosis, Autoantigens, Calcium Signaling, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, Ligands, Mice, Mice, Inbred C57BL, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Proteins, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, Thymocytes