Abstract
T cell receptor (TCR) activation is modulated by mechanisms such as TCR endocytosis, which is thought to terminate TCR signalling. Here we show that, upon internalization, TCR continues to signal from a set of specialized endosomes that are crucial for T cell functions. Mechanistically, TCR ligation leads to clathrin-mediated internalization of the TCR-CD3ζ complex, while maintaining CD3ζ signalling, in endosomal vesicles that contain the insulin responsive aminopeptidase (IRAP) and the SNARE protein Syntaxin 6. Destabilization of this compartment through IRAP deletion enhances plasma membrane expression of the TCR-CD3ζ complex, yet compromises overall CD3ζ signalling; moreover, the integrity of this compartment is also crucial for T cell activation and survival after suboptimal TCR activation, as mice engineered with a T cell-specific deletion of IRAP fail to develop efficient polyclonal anti-tumour responses. Our results thus reveal a previously unappreciated function of IRAP-dependent endosomal TCR signalling in T cell activation.
Highlights
Tcell receptor (TCR) activation is modulated by mechanisms such as TCR endocytosis, which is thought to terminate TCR signalling
To determine if the ζ chain is targeted to insulin responsive aminopeptidase (IRAP)/Syntaxin 6 (Stx6)+ vesicles via the secretory pathway or from the cell surface, we screened for molecules possibly involved in ζ chain and IRAP endocytosis
We found that CD3ζ and IRAP were constitutively transported to the cell surface, but were internalized in IRAP-dependent endosomes characterised by the Stx[6] marker via an endocytosis pathway that depended on the clathrin adaptor AP2 and DnM2 (Fig. 1h; Supplementary Fig. 1e–h)
Summary
Tcell receptor (TCR) activation is modulated by mechanisms such as TCR endocytosis, which is thought to terminate TCR signalling. In the absence of IRAP, CD3ζ accumulated at the plasma membrane and increased cell surface expression of CD3ε and TCR complex (Fig. 1i–k). We hypothesised that the defective TCR signalling observed in IRAP-deficient cells could be attributed to CD3ζ depletion from the intracellular pools (Fig. 1e, f).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
