To eliminate infected or tumor cells, the body mobilizes adaptive immunity, in which T lymphocytes are central players. To become activated, a T lymphocyte uses its antigen receptor (the TCR complex) to recognize fragments of proteins presented by major histocompatibility complex molecules on the surface of another cell, at a contact zone called the immunological synapse. The TCR complex brings together several chains, including a homodimer of ζ chains. Essential for surface expression of the receptor, the ζ chain also carries three ITAM-type activation motifs, compared with only one for the other chains, giving it a major role in signal transduction. The TCR components are distributed across several intracellular compartments, but the nature of the one harboring the ζ chain remained unknown.
This News article presents work showing that this compartment is defined by IRAP, an aminopeptidase already described in adipocytes and dendritic cells. A dual-function protein, IRAP has enzymatic activity and also controls endosome mobility through its interaction with the actin cytoskeleton. The ζ chain is found in endosomes containing IRAP, syntaxin 6 and the small GTPase Rab4, which move toward the synapse upon activation; IRAP interacts with the ζ chain and with the kinase Lck, and the ζ chain reaches these endosomes via AP-2- and dynamin 2-dependent endocytosis.
In the absence of IRAP, the TCR complex accumulates at the surface of the lymphocytes, but their signaling collapses and interleukin 2 secretion decreases. Imaging of the synapse reveals defective recruitment of signaling proteins, and a biosensor coupling the ζ chain to the kinase ZAP70 shows that signaling persists at the membrane but is extinguished in the endosomes. In a normal cell, this compartment continuously replenishes the synapse with ζ chains; without IRAP, the synapse remains frozen. This association furthermore requires the S-acylation of IRAP.
In mice, T lymphocytes lacking IRAP display the same defect, which is more pronounced in response to a low-affinity antigen: they divide normally but then fail to survive. The deficient mice are lymphopenic, whereas their thymic development is normal, pointing to a survival defect in the secondary lymphoid organs, probably linked to the weakening of the tonic signal maintained by self antigens. Finally, mice lacking IRAP solely in their T lymphocytes allow tumors to grow more and recruit fewer CD8+ T lymphocytes into the tumor. These findings could shed light on the signaling of other ITAM-motif receptors and help improve T-lymphocyte-based immunotherapies.