Differential stem-like potential of naïve and memory CD8 T cells after chronic infection.

Memory CD8 T cells respond rapidly upon antigen re-encounter and are considered advantageous for protective immunity. However, they undergo a swift decline under chronic antigen stimulation. In this study, we found that memory CD8 T cells' heightened activation sensitivity promotes terminal differentiation and impairs the formation of CXCR5+Tim-3- progenitor subsets, resulting in reduced persistence. This defect was commonly observed in memory CD8 T cells generated by diverse immunization strategies. Mechanistically, their inability to generate progenitor cells was not due to insufficient expression of TCF1 or TOX upregulation. Importantly, blockade of type I interferon signaling during priming restored progenitor differentiation of secondary activated CD8 T cells. These findings highlight that the activation context of memory CD8 T cells critically influences their fate during persistent infection and suggest that modulating inflammatory signals may enhance the durability of secondary responses.