Control of T cell antigen reactivity via programmed TCR downregulation

The T cell receptor (TCR) is unique in that its affinity for ligand is unknown prior to encounter and can vary by orders of magnitude. How the immune system regulates individual T cells that display highly different reactivity to antigen remains unclear. Here we identified that activated CD4(+) T cells, at the peak of clonal expansion, persistently downregulate TCR expression in proportion to the strength of initial antigen recognition. This programmed response increases the threshold for cytokine production and recall proliferation in a clone-specific manner, ultimately excluding clones with the highest antigen reactivities. Thus, programmed TCR downregulation represents a negative feedback mechanism to constrain T cell effector function with a suitable time delay, thereby allowing pathogen control while avoiding excess inflammatory damage.