| First Author | Fu G | Year | 2013 |
| Journal | Nature | Volume | 504 |
| Issue | 7480 | Pages | 441-5 |
| PubMed ID | 24226767 | Mgi Jnum | J:207761 |
| Mgi Id | MGI:5559611 | Doi | 10.1038/nature12718 |
| Citation | Fu G, et al. (2013) Themis sets the signal threshold for positive and negative selection in T-cell development. Nature 504(7480):441-5 |
| abstractText | 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 CD8alphabeta-expressing 'single-positive' thymocytes from CD4(+)CD8alphabeta(+) '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. |
