PTPN22 interacts with EB1 to regulate T-cell receptor signaling

The PTPN22 gene encoding the Lyp/Pep protein tyrosine phosphatase is a negative regulator of T-cell receptor (TCR) signaling. Recent studies have shown that phosphorylation of end-binding protein 1 (EB1) is associated with the TCR activation. In this study, using 2-hybrid and mass spectrometry analyses, we identified EB1 as a protein associated with PTPN22. Furthermore, we discovered that EB1 specifically bound to the P1 domain of PTPN22 by competing with CSK, and the variant PTPN22-R620W does not affect the association with EB1, which is instrumental with respect to the regulation of TCR signaling. In addition, PTPN22 dephosphorylates EB1 at tyrosine-247 (Y247), which decreases the expression of the T-cell activation markers CD25 and CD69 and the phosphorylation levels of the TCR molecules ZAP-70, LAT, and Erk, leading to the eventual downregulation of the transcription factor NFAT and reduced the levels of secreted IL-2. The findings of this study provide new insights into the TCR signaling and the T-cell immune response, which are important for clarifying the mechanism of PTPN22-related autoimmune diseases.