IL-7 signaling must be intermittent, not continuous, during CD8 T cell homeostasis to promote cell survival instead of cell death

Maintenance of naive CD8 T cells is necessary for lifelong immunocompetence but for unknown reasons requires both interleukin-7 (IL-7) and T cell receptor (TCR) signaling. We now report that naive CD8 T cells require IL-7 signaling to be intermittent, not continuous, because prolonged IL-7 signaling induces naive CD8 T cells to proliferate, produce interferon-γ (IFN-γ), and undergo IFN-γ-triggered cell death. Homeostatic TCR engagements interrupt IL-7 signaling and thereby support CD8 T cell survival and quiescence. However, CD8 T cells with insufficient TCR affinity for self-ligands receive prolonged IL-7 signaling and die during homeostasis. This study identifies the regulation of IL-7 signaling duration by homeostatic TCR engagements as the basis for in vivo CD8 T cell homeostasis.