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TcR-ligand interaction

Kinetics of the T cell receptor (TcR)-ligand interaction and T cell stimulation.

Whereas the interaction between an individual TcR and its ligand occurs over a time frame of a few seconds, the interaction between a single T cell-APC pair has a time course of several hours. This long-lasting contact is necessary to ensure the sustained signaling that maintains gene transcription and promotes T cell cycle progression.

A few (~100 per APC) agonistic peptide-MHC complexes engage and trigger, with time, a much larger number of TcRs (~20,000 per T cell). This serial triggering process implies that effective agonists must be able not only to engage and trigger, but also to dissociate from the triggered TcR to become available for a new interaction.

The capacity to induce TcR downregulation correlates with the capacity to activate T cell. Thus, strong agonists induce higher levels of downregulation than weak agonists, while antagonists fail to downregulate TcRs, but competitively inhibit TcR downregulation induced by agonists [1].

Irrespective of the nature and affinity of the ligand, T cells are activated to proliferate and produce cytokines when a threshold number of triggered TcRs is reached. In human T cell clones that express ~30,000 TcRs, the treshold has been estimated to be ~8000 TcRs in the absence and ~1000 TcRs in the presence of CD28-mediated costimulation.

While effector T cells are rapidly committed to proliferate, naïve T cells must be stimulated for several hours, which may reflect their need to increase size before entering the cell cycle. The required duration of signalling is dependent on the amount of antigen and the presence of costimulation. When high doses of antigens are presented by professional APC, naïve T cells become committed after 6hr; however, at lower antigen doses, or when costimulation is lacking, the duration of stimulation needs to be increased up to 30hr.

TcR and BcR share the property of being downregulated and degraded upon triggering. In B cells this mechanism plays the essential role of delivering antigen to the processing compartment, while in T cells the role of TcR degradation remains a matter of speculation.

[1] Lanzavecchia, A. et al. Cell, 96, 1-4 (1999).