Collaboration between IL-7 and IL-15 enables adaptation of tissue-resident and circulating memory CD8+ T cells 2148

Abstract Description 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 (TRM) subsets. Furthermore, the cell-intrinsic requirement for IL-7 signaling during memory homeostasis has not been directly tested. Using inducible deletion in multiple models of CD8+ T cell memory, we found that Il7ra loss had only a modest effect on persistence of established circulating and resident memory subsets. 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 TRM populations previously described as IL-15-independent. In the absence of IL-15 signaling, IL-7Rα was upregulated, and loss of IL-7Rα reduced proliferation in response to IL-15, suggesting cross-regulation in memory CD8+ T cells. Our results resolve that IL-15-independent CD8+ T cell memory is explained by compensatory IL-7 signaling, leading to a new model. 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. Funding Sources Supported by the Damon Runyon Cancer Research Foundation (DRG-2427-21); NIAID (1K22AI177360-01; T32 AI007313; R01 AI038903), NCI (F30 CA250321; K00 CA245735). Topic Categories Mucosal and Regional Immunology (MUC)