Sensing of ATP via the Purinergic Receptor P2RX7 Promotes CD8+ Trm Cell Generation by Enhancing Their Sensitivity to the Cytokine TGF-β

Abstract

Tissue-resident memory (Trm) CD8 + T cells mediate protective immunity in barrier tissues, but the cues promoting Trm cell generation are poorly understood. Sensing of extracellular adenosine triphosphate (eATP) by the purinergic receptor P2RX7 is needed for recirculating CD8 + T cell memory, but its role for Trm cells is unclear. Here we showed that P2RX7 supported Trm cell generation by enhancing CD8 + T cell sensing of TGF-b, which was necessary for tissue residency. P2RX7-deficient Trm cells progressively decayed in nonlymphoid tissues and expressed dysregulated Trm-specific markers. P2RX7 was required for efficient reexpression of the receptor TGF-bRII through calcineurin signaling. Forced Tgfbr2 expression rescued P2RX7-deficient Trm cell generation, and TGF-b sensitivity was dictated by P2RX7 agonists and antagonists. Forced Tgfbr2 also rescued P2RX7-deficient Trm cell mitochondrial function. Sustained P2RX7 signaling was required for long-term Trm cell maintenance, indicating that P2RX7 signaling drives induction and CD8 + T cell durability in barrier sites.

Discipline in Stages: Regulating CD8+ Resident Memory T Cells

“…Although P2RX7 promotes CD8 + T RM formation within the intestine (125), Stark et al demonstrated that sterile tissue damage led to loss of established WT, but not P2rx7 −/− CD8 + T RM from the liver (140). They found that TCR triggering downregulates P2RX7 expression, and so proposed that tissue damage-induced depletion of established T RM might free space for the formation of new CD8 + T RM with infection-relevant specificities.…”

“…Upon CD8 + T cell activation, expression of TGF-β receptors is transiently down-regulated. Extracellular ATP derived from intestinal microbiota, activated cells and/or damaged tissue restores TGF-βRII expression and TGF-β responsiveness, resulting in CD8 + T cell CD103 upregulation, KLF2 downregulation, enhanced mitochondrial function and T RM formation ( 125 ). On the other hand, microbiota depletion by antibiotic treatment increases the antigen load following LM infection and promotes CXCR3-directed CD8 + T cell accumulation within the large intestinal lamina propria, resulting in increased mucosal CD8 + T RM accumulation and response ( 126 ).…”

“…Although P2RX7 promotes CD8 + T RM formation within the intestine ( 125 ), Stark et al. demonstrated that sterile tissue damage led to loss of established WT, but not P2rx7 −/− CD8 + T RM from the liver ( 140 ).…”

Functional Heterogeneity and Therapeutic Targeting of Tissue-Resident Memory T Cells

“…In this context, TGF-β signaling in T RM cells can be further modulated via external signals. Sensing of ATP via P2RX7 promotes CD8 + T RM cell generation by enhancing their sensitivity to TGF-β [122]. Moreover, monocyte-produced IL-10 induces the release of surface-bound TGF-β, which in turn induces CD103 upregulation on T cells.…”

P2X7 is a cytotoxic receptor….maybe not: implications for cancer

“…These data show that, albeit the P2X7R is an increasingly appealing target for cancer therapy, more needs to be known about the complex host-tumor interplay of which this receptor is an ineludible player. This picture is further complicated by the recent exciting finding that the P2X7R is implicated in the process of generation of CD8 + memory T cells [46,47], suggesting that its blockade might hamper immunological memory.…”