Complete but curtailed T-cell response to very low-affinity antigen

After an infection, T cells that carry the CD8 marker are activated and undergo a characteristic kinetic sequence of rapid expansion, subsequent contraction and formation of memory cells. The pool of naive T-cell clones is diverse and contains cells bearing T-cell antigen receptors (TCRs) that differ in their affinity for the same antigen. How these differences in affinity affect the function and the response kinetics of individual T-cell clones was previously unknown. Here we show that during the in vivo response to microbial infection, even very weak TCR-ligand interactions are sufficient to activate naive T cells, induce rapid initial proliferation and generate effector and memory cells. The strength of the TCR-ligand interaction critically affects when expansion stops, when the cells exit lymphoid organs and when contraction begins; that is, strongly stimulated T cells contract and exit lymphoid organs later than weakly stimulated cells. Our data challenge the prevailing view that strong TCR ligation is a prerequisite for CD8⁺ T-cell activation. Instead, very weak interactions are sufficient for activation, but strong TCR ligation is required to sustain T-cell expansion. We propose that in response to microbial challenge, T-cell clones with a broad range of avidities for foreign ligands are initially recruited, and that the pool of T cells subsequently matures in affinity owing to the more prolonged expansion of high-affinity T-cell clones.