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

Nature. 2013 Dec 19;504(7480):441-5. doi: 10.1038/nature12718. Epub 2013 Nov 13.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Autoantigens / immunology
  • Calcium Signaling
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Intercellular Signaling Peptides and Proteins
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
  • Proteins / genetics
  • Proteins / metabolism*
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction / immunology*
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • Thymocytes / cytology*
  • Thymocytes / immunology
  • Thymocytes / metabolism*


  • Autoantigens
  • Intercellular Signaling Peptides and Proteins
  • Ligands
  • Proteins
  • Receptors, Antigen, T-Cell
  • themis protein, mouse
  • Extracellular Signal-Regulated MAP Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6