The affinity of T cell antigen receptors (TCRs) for complexes of self peptide and major histocompatibility complex governs thymic selection, but how signal strength is functionally perceived is not clear. In Nature, Gascoigne and colleagues show that themis, a protein coupled to TCR signaling, acts as a signal-threshold converter that leads to positive or negative selection. Themis-deficient CD4+CD8+ thymocytes are more sensitive to low-affinity peptides than are wild-type thymocytes, but their Ca2+ fluxes and responses of phosphorylated kinase Erk to high-affinity agonist peptides are similar to those of wild-type thymocytes. TCR activation in themis-deficient thymocytes triggers less activation of the phosphatases SHP-1 and SHP-2, which associate with themis in wild-type thymocytes, and increased activation of the proapoptotic proteins Bim and caspase-3. Themis-deficient mice exhibit enhanced thymic negative selection. Thus, themis acts to suppress TCR signaling in response to low-affinity ligands and ensures that such 'self-reactive' thymocytes survive and mature to become naive T cells.

Nature (13 November 2013) doi:10.1038/nature12718