Themis controls thymocyte selection through regulation of T cell antigen receptor–mediated signaling

Abstract

The molecular mechanisms that underpin thymocyte selection remain incompletely defined. Groups led by Love, Gascoigne and Schwartz independently identify Themis, a signaling protein essential for the positive selection of thymocytes. Themis (thymocyte-expressed molecule involved in selection), a member of a family of proteins with unknown functions, is highly conserved among vertebrates. Here we found that Themis had high expression in thymocytes between the pre–T cell antigen receptor (pre-TCR) and positive-selection checkpoints and low expression in mature T cells. Themis-deficient thymocytes showed defective positive selection, which resulted in fewer mature thymocytes. Negative selection was also impaired in Themis-deficient mice. A greater percentage of Themis-deficient T cells had CD4+CD25+Foxp3+ regulatory and CD62LloCD44hi memory phenotypes than did wild-type T cells. In support of the idea that Themis is involved in TCR signaling, this protein was phosphorylated quickly after TCR stimulation and was needed for optimal TCR-driven calcium mobilization and activation of the kinase Erk.