T lymphocytes detect the presence of antigens through a specific receptor, the T-cell receptor (TCR), which recognizes peptides presented by major histocompatibility complex molecules (pMHC). The activation of these cells depends closely on the amount of TCR complexes exposed at the cell surface, where signaling is initiated. This amount results from a dynamic equilibrium between receptor synthesis, recycling, and degradation. This review focuses on the role of endocytic trafficking in controlling TCR expression and, more broadly, in modulating its signaling. It first highlights the quantitative importance of this phenomenon: it is estimated that mammalian cells recycle at least half of their plasma membrane within one hour, a turnover far faster than protein synthesis alone, whose half-life ranges from 0.5 to 35 hours in dividing cells.
The authors describe the two main pathways of membrane internalization—clathrin-dependent endocytosis and clathrin-independent endocytosis, the latter encompassing several processes that rely on membrane cholesterol content. They emphasize that a given receptor may use several pathways depending on the cell type, ligand affinity, or ligand concentration, which complicates analysis of the impact of endocytosis on trafficking and signaling. Following pMHC recognition, the TCR forms aggregates and contributes to the establishment of the immunological synapse, a close contact between the lymphocyte and the antigen-presenting cell, from which the activated receptor is internalized.
Long regarded as a mechanism for terminating the signal, this internalization now appears to be a step that can prolong signaling from specialized endosomes. The review brings together the experimental evidence supporting this hypothesis. A FRET reporter, measuring the interaction between the phosphorylated CD3ζ chain and the SH2 domain of ZAP-70, revealed a signal that was not only membrane-associated but also present in intracellular vesicles labeled by Rab5 and Rab11. In addition, the study of dynamin 2–deficient lymphocytes shows a proliferation defect and only transient activation of mTORC1, attributed to decreased expression of c-Myc. Likewise, inactivation of IRAP, which interacts with CD3ζ, abolishes the endosomal signal and reduces phosphorylation of signaling partners as well as IL-2 secretion, despite an accumulation of TCR at the surface.
In conclusion, substantial data indicate that the internalized TCR retains signaling capacity from endosomes, even though the endosomal source of ligands remains to be elucidated, with trogocytosis representing one possibility. The authors suggest that this endosomal signaling would serve to amplify and diversify the signal, and that its characterization could help improve T cell–based immunotherapy strategies.