Collaboration between interleukin-7 and -15 enables adaptation of tissue-resident and circulating memory CD8+ T cells to cytokine deficiency

Abstract

Interleukin-7 (IL-7) is considered a critical regulator of memory CD8⁺ T cell homeostasis. However, this is primarily based on circulating memory populations, and the cell-intrinsic requirement for IL-7 signaling during memory homeostasis has not been directly tested. Here, we addressed the role for IL-7Rα in circulating and resident memory CD8⁺ T cells (Trm) after their establishment. We found that inducible Il7ra deletion had only a modest effect on persistence of circulating memory and Trm subsets, causing reduced basal proliferation. Loss of IL-15 signaling imposed heightened IL-7Rα dependence on memory CD8⁺ T cells, including Trm cells described as IL-15 independent. In the absence of IL-15 signaling, IL-7Rα was elevated, and loss of IL-7Rα signaling reduced IL-15-elicited proliferation, suggesting crosstalk between these pathways 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.