No-shows in T-cell responses are frequent for clones of low T-cell receptor affinity.

The magnitude of CD8 T-cell responses against intracellular pathogens is thought to primarily depend on the expansion capacity of naïve T cells, given that their recruitment is considered optimal. In the current issue of the European Journal of Immunology [Eur. J. Immunol. 2023. 53: 000-000], Leube et al. challenge these concepts and show that the recruitment of naïve T-cell clones into primary responses can be far from complete. The failure to efficiently recruit T-cell clones occurs more frequently in case of low-affinity interactions of the T-cell receptor with cognate antigen of the pathogen. Using single-cell fate-mapping in the Lm-OVA model, the authors demonstrate that naïve T-cell clones of low affinity in contrast to those of high affinity often do not expand after pathogen encounter. These low-affinity clones are maintained as naïve CD8 T cells that can robustly respond upon secondary encounter with the same pathogen, in particular when the reencountered pathogen contains modifications resulting in improved recognition. Thus, this study indicates that the regulation of the response size of CD8 T cells is yet more elaborate than anticipated and involves control at the level of recruitment and expansion of naïve CD8 T cells.