Research ArticleImmunology

Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability

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Sci. Signal.  17 May 2016:
Vol. 9, Issue 428, pp. ra51
DOI: 10.1126/scisignal.aad1576

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Tipping the signaling scales

The strength of the signal produced by the T cell receptor (TCR) in response to self-antigen determines whether an immature thymocyte undergoes positive selection and matures into a T cell or negative selection and is eliminated to avoid autoreactivity. Both selection processes require the protein Themis1. By examining the effects of either loss or overexpression of Themis1 in thymocytes in mice, Zvezdova et al. determined that Themis1 enhances the activity of the guanine nucleotide exchange factor Vav1 and the stability of the TCR-associated adaptor protein Grb2, thus enabling TCR signaling. These data suggest that, although Themis1 also recruits a phosphatase to the TCR complex, the primary role for Themis1 is to enhance rather than inhibit TCR signaling to promote thymocyte development.

Abstract

The T cell signaling protein Themis1 is essential for the positive and negative selection of thymocytes in the thymus. Although the developmental defect that results from the loss of Themis1 suggests that it enhances T cell receptor (TCR) signaling, Themis1 also recruits Src homology 2 domain–containing phosphatase-1 (SHP-1) to the vicinity of TCR signaling complexes, suggesting that it has an inhibitory role in TCR signaling. We used TCR signaling reporter mice and quantitative proteomics to explore the role of Themis1 in developing T cells. We found that Themis1 acted mostly as a positive regulator of TCR signaling in vivo when receptors were activated by positively selecting ligands. Proteomic analysis of the Themis1 interactome identified SHP-1, the TCR-associated adaptor protein Grb2, and the guanine nucleotide exchange factor Vav1 as the principal interacting partners of Themis1 in isolated mouse thymocytes. Analysis of TCR signaling in Themis1-deficient and Themis1-overexpressing mouse thymocytes demonstrated that Themis1 promoted Vav1 activity both in vitro and in vivo. The reduced activity of Vav1 and the impaired T cell development in Themis1−/− mice were due in part to increased degradation of Grb2, which suggests that Themis1 is required to maintain the steady-state abundance of Grb2 in thymocytes. Together, these data suggest that Themis1 acts as a positive regulator of TCR signaling in developing T cells, and identify a mechanism by which Themis1 regulates thymic selection.

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