Long‐lived memory CD8+ T cells are programmed by prolonged antigen exposure and low levels of cellular activation

AbstractCD8+ T cells play a crucial role in controlling intracellular pathogens. The level of memory CD8+ T cells developing after vaccination or infection influences the degree of T cell‐mediated protection after secondary infection. We used defined animal models and infections/immunizations by replicating or non‐replicating antigens to define on a molecular and cellular level in vivo the parameters that identify and shape long‐lived CD8+ T cell memory. We show that the timing of antigen exposure during vaccination is key for the induction of long‐lived T cell memory. Brief antigen exposure induced high numbers of effector cells but limited development of long‐lived CD8+ memory T cells. In contrast, prolonged antigen exposure for up to 9 days induced similar numbers of effector T cells but additionally resulted in high levels of memory CD8+ T cells. Unexpectedly CD127 (IL‐7Rα) expression on CD8+ T cells during the acute priming phase was a necessary but not sufficient requirement for entering the pool of long‐lived antigen‐independent memory CD8+ T cells. However, we provide strong evidence for the interpretation that programming of long‐lived memory T cells was driven by low levels of transcription factor eomesodermin and protease inhibitor Spi2A as well as reduced phosphorylation of c‐JUN.