The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells

Silva, Henrique Borges da; Beura, Lalit K.; Wang, Haiguang; Hanse, Eric A.; Gore, Reshma; Scott, Milcah C.; Walsh, Daniel; Block, Katharine E.; Fonseca, Raíssa; Yan, Yan; Hippen, Keli L.; Blazar, Bruce R.; Masopust, David; Kelekar, Ameeta; Vulchanova, Lucy; Hogquist, Kristin A.; Jameson, Stephen C.

doi:10.1038/s41586-018-0282-0

Cited by 207 publications

(242 citation statements)

References 46 publications

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“…We recently reported that expression of P2RX7 is necessary for T RM development in nonlymphoid tissues (7). Superficially, this appears to be at odds with the increased susceptibility to NAD-induced cell death for T RM described in this article.…”

Section: Artc22 Blockade Improves the Yield Of Nkt1 Cells In Nonlympmentioning

confidence: 67%

“…Extracellular ATP (eATP) stimulates P2RX7, which is a nonselective ligand-gated ion channel expressed by several immune cell types. Prior research focused on myeloid cells (2,3), but P2RX7 is also expressed by lymphocyte populations (4)(5)(6)(7). When activated by high concentrations of eATP, P2RX7 forms reversible nonselective pores that can mediate activation signals but can ultimately lead to cell death if eATP exposure persists (2,8).…”

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confidence: 99%

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ARTC2.2/P2RX7 Signaling during Cell Isolation Distorts Function and Quantification of Tissue-Resident CD8+ T Cell and Invariant NKT Subsets

Silva

Wang

Qian

et al. 2019

The Journal of Immunology

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Peripheral invariant NKT cells (iNKT) and CD8+ tissue-resident memory T cells (TRM) express high levels of the extracellular ATP receptor P2RX7 in mice. High extracellular ATP concentrations or NAD-mediated P2RX7 ribosylation by the enzyme ARTC2.2 can induce P2RX7 pore formation and cell death. Because both ATP and NAD are released during tissue preparation for analysis, cell death through these pathways may compromise the analysis of iNKT and CD8+ TRM. Indeed, ARTC2.2 blockade enhanced recovery of viable liver iNKT and TRM. The expression of ARTC2.2 and P2RX7 on distinct iNKT subsets and TRM is unclear, however, as is the impact of recovery from other nonlymphoid sites. In this study, we performed a comprehensive analysis of ARTC2.2 and P2RX7 expression in iNKT and CD8+ T cells in diverse tissues, at steady-state and after viral infection. NKT1 cells and CD8+ TRM express high levels of both ARTC2.2 and P2RX7 compared with NKT2, NKT17, and CD8+ circulating memory subsets. Using nanobody-mediated ARTC2.2 antagonism, we showed that ARTC2.2 blockade enhanced NKT1 and TRM recovery from nonlymphoid tissues during cell preparation. Moreover, blockade of this pathway was essential to preserve functionality, viability, and proliferation of both populations. We also showed that short-term direct P2RX7 blockade enhanced recovery of TRM, although to a lesser degree. In summary, our data show that short-term in vivo blockade of the ARTC2.2/P2RX7 axis permits much improved flow cytometry–based phenotyping and enumeration of murine iNKT and TRM from nonlymphoid tissues, and it represents a crucial step for functional studies of these populations.

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Section: Artc22 Blockade Improves the Yield Of Nkt1 Cells In Nonlympmentioning

confidence: 67%

mentioning

confidence: 99%

ARTC2.2/P2RX7 Signaling during Cell Isolation Distorts Function and Quantification of Tissue-Resident CD8+ T Cell and Invariant NKT Subsets

Silva

Wang

Qian

et al. 2019

The Journal of Immunology

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“…250,251 Furthermore, P2RX7 activates AMPK and restrains mTOR activation to promote memory CD8 + T-cell function, and transient P2RX7 blockade at the memory stage compromises the maintenance of memory CD8 + T cells. 252 Together, these results indicate that memory CD8 + T-cell fate is not an entirely default program but is an active process requiring regulatory networks, such as mTORC1 and mTORC2 signaling, to fix their lineage maturation.…”

Section: Mtor Signaling In Effector-cell Maintenance and Transdiffementioning

confidence: 85%

mTOR signaling at the crossroads of environmental signals and T‐cell fate decisions

Huang

Long

Zhou

et al. 2020

Immunological Reviews

123

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The evolutionarily conserved serine/threonine kinase mTOR (mechanistic target of rapamycin) forms the distinct protein complexes mTORC1 and mTORC2 and integrates signals from the environment to coordinate downstream signaling events and various cellular processes. T cells rely on mTOR activity for their development and to establish their homeostasis and functional fitness. Here, we review recent progress in our understanding of the upstream signaling and downstream targets of mTOR. We also provide an updated overview of the roles of mTOR in T‐cell development, homeostasis, activation, and effector‐cell fate decisions, as well as its important impacts on the suppressive activity of regulatory T cells. Moreover, we summarize the emerging roles of mTOR in T‐cell exhaustion and transdifferentiation. A better understanding of the contribution of mTOR to T‐cell fate decisions will ultimately aid in the therapeutic targeting of mTOR in human disease.

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“…Meanwhile, the transition to the memory T cell fate is associated with the inhibition of PI3K/mTORC1 signaling and silencing of aerobic glycolysis by AMP-activated protein kinase (AMPK) in favor of mitochondrial biogenesis and fusion 8,14,15,16 , which is mediated by peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1a) 11,17 .…”

Section: Introductionmentioning

confidence: 99%

Single-cell metabolic dynamics of early activated CD8 T cells during the primary immune response to infection

Levine

Hiam

Márquez

et al. 2020

Preprint

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Mass cytometry permits high-dimensional analysis of diverse aspects of cellular behavior. Here, we adapted this platform to simultaneously profile metabolism, signaling, cell cycle, and effector function with single-cell resolution. Using this approach, we measured enzymes characterizing glycolysis, the TCA cycle, fatty acid oxidation, oxidative phosphorylation, and nutrient transport.In conjunction, we measured downstream targets of TCR signaling regulating translation, proliferation and cytotoxicity as well as surface markers and transcription factors delineating CD8 T cell differentiation. High-dimensional single-cell metabolic analysis by mass cytometry permits identification of unique metabolic and differentiation states of extremely rare cell populations, such as antigen-specific T cells. We interrogated antigen-specific CD8 T cell activation in vitro as well as the trajectory of CD8 T cells responding to Listeria monocytogenes infection, a well-characterized model for studies of T cell differentiation. This integrated, highdimensional approach revealed a novel, activated, and highly metabolically active transitional T cell subset emerging at four days post-infection. These cells simultaneously exhibit glycolytic and oxidative functional programs, which we propose represents a key metabolic inflection point in CD8+ T cell differentiation. This approach should be useful for mechanistic investigations of metabolic regulation of immune responses in vivo.Recombinant human IL-2 (IL-2; TECIN (Teceleukin)) was provided by the National Cancer Institute.

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The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells

Cited by 207 publications

References 46 publications

ARTC2.2/P2RX7 Signaling during Cell Isolation Distorts Function and Quantification of Tissue-Resident CD8+ T Cell and Invariant NKT Subsets

ARTC2.2/P2RX7 Signaling during Cell Isolation Distorts Function and Quantification of Tissue-Resident CD8+ T Cell and Invariant NKT Subsets

mTOR signaling at the crossroads of environmental signals and T‐cell fate decisions

Single-cell metabolic dynamics of early activated CD8 T cells during the primary immune response to infection

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