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

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Abstract
According to the prevailing view, high-affinity T-cell receptor (TCR) ligation is required for T-cell priming and thymic negative selection, while low-affinity ligands induce positive selection and lymphopaenia-driven homeostatic expansion. Zehn et al. report that, surprisingly, T-cell expansion after initial activation occurs irrespective of TCR affinity. Low-affinity cells generate functional effector and memory responses. However, their expansion ceases earlier resulting in an overall decreased total number of low-affinity cells compared to their high-affinity counterparts. The findings have implications for autoimmunity and the makeup of the memory T-cell pool. This paper reports the observation that T-cell expansion after initial activation occurs irrespective of TCR affinity. Low-affinity cells generate functional effector and memory responses; however, their expansion ceases earlier, resulting in an overall decreased total number of low-affinity cells compared to their high-affinity counterparts. 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 cells1,2,3. 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 antigen4,5. 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.