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

Abstract

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, we found that Il7ra loss had only a modest effect on persistence of circulating memory and TRM subsets and that IL-7R was primarily required for normal basal proliferation. Loss of IL-15 signaling imposed heightened IL-7R dependence on memory CD8+ T cells, including TRM populations previously described as IL-15-independent. In the absence of IL-15 signaling, IL-7R was upregulated, and loss of IL-7R 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. HighlightsTissue-resident and circulating memory CD8+ T cells modestly decline after loss of IL-7R IL-7R 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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=70 SRC="FIGDIR/small/596695v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@8e439corg.highwire.dtl.DTLVardef@1f8e42forg.highwire.dtl.DTLVardef@14cfceforg.highwire.dtl.DTLVardef@171e4eb_HPS_FORMAT_FIGEXP M_FIG C_FIG