TCR Trafficking in Resting and Stimulated T Cells

Dynamic regulation of TCR expression levels plays important roles in modulating T-cell responses during T-cell development and in mature T cells. TCR expression levels are determined by the rate constants for synthesis, endocytosis, recycling, and degradation. This review examines the rate constants, the molecular mechanisms, and the proposed physiological roles of TCR trafficking in resting and stimulated T cells. In resting T cells, the TCR slowly and constitutively cycles between the plasma membrane and the intracellular compartment. Constitutive TCR cycling is dependent on the di-leucine-based (diL) receptor-sorting motif in the TCR subunit CD3g and might play a role in quality control of the TCR. TCR triggering induces an enhancement in the endocytic rate constant leading to TCR down-regulation. At least two pathways exist for endocytosis of triggered TCR. One is dependent on protein tyrosine kinase activity leading to ubiquitination of the TCR, whereas the other is dependent on protein kinase C (PKC)-mediated activation of the diL motif. In addition, nontriggered TCR are endocytosed (co-modulated) by the PKC/CD3g-dependent pathway. TCR down-regulation might attenuate signaling and/or might ensure an internal store of TCR that can be rerouted to the immunological synapse during the encounter with an antigen-presenting cell.