Biology subjects

Wanhainen, K. M.

Publications and source records attributed to Wanhainen, K. M..

3 recordsLinked to original sources

bioRxiv2024

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

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

immunology↗

bioRxiv2023

Pannexin-1 channels promote CD8+ T cell effector and memory responses through distinct intracellular pathways

Sensing of extracellular ATP (eATP) controls CD8+ T cell function. Their accumulation can occur through export by specialized molecules, such as the release channel Pannexin-1 (Panx1). Whether Panx1 controls CD8+ T cell immune responses in vivo, however, has not been previously addressed. Here, we report that T cell-specific Panx1 is needed for CD8+ T cell responses to viral infections and cancer. We found that CD8-specific Panx1 promotes both effector and memory CD8+ T cell responses. Panx1 favors initial effector CD8+ T cell activation through extracellular ATP (eATP) export and subsequent P2RX4 activation, which helps promote full effector differentiation through extracellular lactate accumulation and its subsequent recycling. In contrast, Panx1 promotes memory CD8+ T cell survival primarily through ATP export and subsequent P2RX7 engagement, leading to improved mitochondrial metabolism. In summary, Panx1-mediated eATP export regulates effector and memory CD8+ T cells through distinct purinergic receptors and different metabolic and signaling pathways.

immunology↗

bioRxiv2021

The extracellular ATP receptor P2RX7 imprints a pro-memory transcriptional signature in effector CD8+ T cells

Development of central memory (Tcm) and resident memory (Trm) CD8+ T cells, which respectively promote immunity in the circulation and in barrier tissues, is not completely understood. Tcm and Trm cells may arise from common precursors, however their fate-inducing signals are elusive. We found that virus-specific effector CD8+ T cells display heterogeneous expression of the extracellular ATP sensor P2RX7. P2RX7-high expression is confined, at peak effector phase, to CD62L+ memory precursors which preferentially form Tcm cells. Among early effector CD8+ T cells, asymmetrical P2RX7 distribution correlated with distinct transcriptional signatures, with P2RX7-high cells enriched for memory and tissue-residency sets. P2RX7-high early effectors preferentially form both Tcm and Trm cells. Defective Tcm and Trm formation in P2RX7 deficiency is significantly reverted when the transcriptional repressor Zeb2 is ablated. Our study indicates that unequal P2RX7 upregulation in effector CD8+ T cells is a foundational element of the early Tcm/Trm fate.

immunology↗