CD27 costimulation promotes IL-7Rα re-expression in effector CD8+ T cells by transcriptional regulation and enhances memory precursor population during acute viral infection (IRC5P.463)

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Abstract IL-7 plays a critical role in the generation and maintenance of memory CD8+ T cells, and IL-7Rα has been regarded as a defining marker of long-lived memory precursor effector cells. While IL-7Rα is downreguated acutely upon TCR stimulation, little is known about the stimuli that promote the recovery of IL-7Rα in Ag-activated CD8+ T cells. Using vaccinia virus, we previously demonstrated that CD27 costimulation during primary response is critical for the generation of IL-7Rα-expressing effectors and promotes CD8+ T cell memory. By utilizing agonistic mAb and transgenic models, here we show 1) direct CD27 stimulation on CD8+ T cells is sufficient and necessary to enhance IL-7Rα-expressing effectors; 2) CD27 stimulation neither alleviates the downregulation of IL-7Rα upon TCR signaling nor promotes the expansion/survival of IL-7Rα-expressing effectors, but facilitates IL-7Rα re-expression; 3) CD27 stimulation regulates Il7ra transcription but not protein distribution. Importantly, CD27 stimulation promotes not only IL-7Rα, but also the common γ chain of the receptor and the downstream signaling mediated by pSTAT5. Intriguingly, stimulation of other TNFSF members OX-40 and 4-1BB showed limited ability to promote IL-7Rα. Our results provide insights into the mechanistic basis by which CD27 costimulation influences CD8+ T cell memory differentiation, and highlight the potential of targeting CD27-CD70 axis to enhance IL-7 signaling for antiviral/antitumor immunotherapy.