SUMMARY Interleukin-7 (IL-7) is considered a critical regulator of memory CD8 + T cell homeostasis, but this is primarily based on analysis of circulating and not tissue-resident memory (T RM ) subsets. Furthermore, the cell-intrinsic requirement for IL-7 signaling during memory homeostasis has not been directly tested. Using inducible deletion, we found that Il7ra loss had only a modest effect on persistence of circulating memory and T RM subsets and that IL-7Rα was primarily required for normal basal proliferation. Loss of IL-15 signaling imposed heightened IL-7Rα dependence on memory CD8 + T cells, including T RM populations previously described as IL-15-independent. In the absence of IL-15 signaling, IL-7Rα was upregulated, and loss of IL-7Rα signaling reduced proliferation in response to IL-15, suggesting cross-regulation in memory CD8 + T cells. Thus, across subsets and tissues, IL-7 and IL-15 act in concert to support memory CD8 + T cells, conferring resilience to altered availability of either cytokine. Highlights Tissue-resident and circulating memory CD8 + T cells modestly decline after loss of IL-7Rα IL-7Rα is required for normal self-renewal of memory CD8 + T cells Combined loss of IL-7 and IL-15 causes a profound defect across memory CD8 + T cell subsets Cross-regulation of IL-7 and IL-15 signaling occurs in memory CD8 + T cells Abstract Figure

Collaboration between IL-7 and IL-15 enables adaptation of tissue-resident and circulating memory CD8+T cells