Abstract
The adaptor protein TNF receptor associated factor (TRAF) 3 is required for effective TCR signaling and normal T cell effector functions, and associates with the CD3/CD28 complex upon activation. To determine how TRAF3 promotes proximal TCR signaling, we studied TRAF3-deficient mouse and human T cells, which showed a marked reduction in activating phosphorylation of the TCR-associated kinase Lck. The impact of TRAF3 on this very early signaling event led to the hypothesis that TRAF3 restrains one or both of two known inhibitors of Lck, C-terminal Src kinase (Csk) and protein tyrosine phosphatase N22 (PTPN22). TRAF3 associated with Csk, promoting the dissociation of Csk from the plasma membrane. TRAF3 also associated with and regulated the TCR/CD28 induced localization of PTPN22. Loss of TRAF3 resulted in increased amounts of both Csk and PTPN22 in T cell membrane fractions and decreased association of PTPN22 with Csk. These findings identify a new role for T cell TRAF3 in promoting T cell activation, by regulating localization and functions of early TCR signaling inhibitors.
Highlights
The adaptor protein TRAF3 regulates effector functions in both CD4+ and CD8+ T cells, enhancing TCR signaling without altering overall numbers of mature T cells[1]
To address our goal of understanding how TRAF3 enhances early TCR signaling, we examined whether more proximal signaling events were affected by a deficiency of TRAF3
To further address the potential role of TRAF3 in protein tyrosine phosphatase N22 (PTPN22) trafficking within intact T cells, we examined PTPN22 localization in mouse splenic T cells stimulated with plate bound αCD3/αCD28 Abs, using Total Internal Reflection Fluorescence (TIRF) microscopy (Fig. 5b)
Summary
The adaptor protein TRAF3 regulates effector functions in both CD4+ and CD8+ T cells, enhancing TCR signaling without altering overall numbers of mature T cells[1]. We hypothesized that TRAF3 promotes Lck activation and downstream events of early TCR signaling by regulating two key Lck inhibitors, Csk and PTPN22. We addressed this hypothesis using primary splenic T cells from T-traf3−/− mice and their WT littermate controls (LMC), as well as a complementary model of human T cell lines and TRAF3-deficient subclones that we produced. In TRAF3-deficient T cells, activation of Lck, as determined by Tyr[394] phosphorylation, was consistently reduced This suggested that the overall reduction in TCR signaling and TCR-dependent downstream functions in these T cells is primarily a consequence of this initial decrease in Lck activation. In TRAF3-deficient T cells, decreased Lck activation levels coincided with an increase in Csk at the plasma membrane
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