Complete but curtailed T cell response to very low affinity antigen

Abstract

Following an infection, CD8 ⁺ T cells are activated and undergo a characteristic kinetic sequence of rapid expansion, subsequent contraction and formation of memory cells 1– 3. The pool of naïve T cell clones is diverse and contains cells bearing T cell antigen receptors (TCR) that differ in their affinity for the same antigen 4, 5. How these differences in affinity impact 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 naïve T cells, induce rapid initial proliferation and generate effector and memory cells. The strength of the TCR-ligand interaction critically impacts when expansion stops, when the cells exit lymphoid organs and when contraction begins, i.e. strongly stimulated T cells contract and exit lymphoid organs later than do weakly stimulated cells. Our data challenges 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 due to the more prolonged expansion of high affinity T cell clones.