THEMIS increases TCR signaling in CD4CD8 thymocytes by inhibiting the activity of the tyrosine phosphatase SHP1.

The T cell lineage-restricted protein THEMIS plays a critical role in T cell development at the positive selection stage. In the SHP1 activation model, THEMIS is proposed to enhance the activity of the tyrosine phosphatase SHP1 (encoded by ), thereby dampening T cell antigen receptor (TCR) signaling and preventing the inappropriate negative selection of CD4CD8 thymocytes by positively selecting ligands. In contrast, in the SHP1 inhibition model, THEMIS is proposed to suppress SHP1 activity, rendering CD4CD8 thymocytes more sensitive to TCR signaling initiated by low-affinity ligands to promote positive selection. We sought to resolve the controversy regarding the molecular function of THEMIS. We found that the defect in positive selection in thymocytes was ameliorated by pharmacologic inhibition of SHP1 or by deletion of and was exacerbated by SHP1 overexpression. Moreover, overexpression of SHP1 phenocopied the developmental defect, whereas deletion of , (encoding SHP2), or both did not result in a phenotype resembling that of deficiency. Last, we found that thymocyte negative selection was not enhanced but was instead impaired in the absence of THEMIS. Together, these results provide evidence favoring the SHP1 inhibition model, supporting a mechanism whereby THEMIS functions to enhance the sensitivity of CD4CD8 thymocytes to TCR signaling, enabling positive selection by low-affinity, self-ligand-TCR interactions.