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-CD3ζcomplex, while maintaining CD3ζsignalling, 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-CD3ζcomplex, yet compromises overall CD3ζsignalling; 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.

Antigen T cell receptors (TCR) recognize antigenic peptides displayed by the major histocompatibility complex (pMHC) and play a critical role in T cell activation. The levels of TCR complexes at the cell surface, where signaling is initiated, depend on the balance between TCR synthesis, recycling and degradation. Cell surface TCR interaction with pMHC leads to receptor clustering and formation of a tight T cell-APC contact, the immune synapse, from which the activated TCR is internalized. While TCR internalization from the immune synapse has been initially considered to arrest TCR signaling, recent evidence support the hypothesis that the internalized receptor continues to signal from specialized endosomes. Here, we review the molecular mechanisms of TCR endocytosis and recycling, both in steady state and after T cell activation. We then discuss the experimental evidence in favor of endosomal TCR signaling and its possible consequences on T cell activation.

Cell surface receptor internalization can either terminate signaling or activate alternative endosomal signaling pathways. We investigated here whether endosomal signaling is involved in the function of the human receptors for Fc immunoglobulin fragments (FcRs): FcαRI, FcγRIIA, and FcγRI. All these receptors were internalized after their cross-linking with receptor-specific antibodies, but their intracellular trafficking was different. FcαRI was targeted directly to lysosomes, while FcγRIIA and FcγRI were internalized in particular endosomal compartments described by the insulin esponsive minoeptidase (IRAP), where they recruited signaling molecules, such as the active form of the kinase Syk, PLCγ and the adaptor LAT. Destabilization of FcγR endosomal signaling in the absence of IRAP compromised cytokine secretion downstream FcγR activation and macrophage ability to kill tumor cells by antibody-dependent cell-mediated cytotoxicity (ADCC). Our results indicate that FcγR endosomal signaling is required for the FcγR-driven inflammatory reaction and possibly for the therapeutic action of monoclonal antibodies.