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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
T cell
T-Lymphocytes Receptors Antigen T-Cell chemical and pharmacologic phenomena Apoptosis Major histocompatibility complex Ligands Autoantigens Article 03 medical and health sciences Negative selection Mice 0302 clinical medicine Antigen medicine Animals Calcium Signaling Receptor Extracellular Signal-Regulated MAP Kinases 030304 developmental biology 0303 health sciences Multidisciplinary Thymocytes biology Protein Tyrosine Phosphatase Non-Receptor Type 6 T-cell receptor Proteins Cell biology Enzyme Activation Mice Inbred C57BL medicine.anatomical_structure Immunology biology.protein Intercellular Signaling Peptides and Proteins Signal transduction Central tolerance 030215 immunology Signal Transduction |
| 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 |
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