THEMIS enhances TCR signaling and enables positive selection by selective inhibition of SHP-1

THEMIS, a T cell specific protein that is highly expressed in CD4(+)CD8(+) thymocytes, has a crucial role in positive selection and T cell development. THEMIS lacks defined catalytic domains but contains two tandem repeats of a distinctive (CABIT) module of unknown function. Here, we show that THEMIS directly regulated the catalytic activity of the protein tyrosine phosphatase SHP-1. This action was mediated by the CABIT modules, which bound to the SHP-1 phosphatase domain and promoted or stabilized oxidation of the SHP-1 catalytic cysteine, inhibiting SHP-1 tyrosine phosphatase activity. Reduction of SHP-1 alleviated the developmental block in Themis(−/−) thymocytes. Thus, THEMIS facilitates thymocyte positive selection by enhancing the T cell antigen receptor signaling response to low affinity ligands.