Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Nature (London), 2018-07, Vol.559 (7713), p.264-268

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• Extracellular ATP (eATP) is an ancient ‘danger signal’ used by eukaryotes to detect cellular damage 1 . In mice and humans, the release of eATP during inflammation or injury stimulates both innate immune activation and chronic pain through the purinergic receptor P2RX7 2 – 4 . It is unclear, however, whether this pathway influences the generation of immunological memory, a hallmark of the adaptive immune system that constitutes the basis of vaccines and protective immunity against re-infection 5 , 6 . Here we show that P2RX7 is required for the establishment, maintenance and functionality of long-lived central and tissue-resident memory CD8 + T cell populations in mice. By contrast, P2RX7 is not required for the generation of short-lived effector CD8 + T cells. Mechanistically, P2RX7 promotes mitochondrial homeostasis and metabolic function in differentiating memory CD8 + T cells, at least in part by inducing AMP-activated protein kinase. Pharmacological inhibitors of P2RX7 provoked dysregulated metabolism and differentiation of activated mouse and human CD8 + T cells in vitro, and transient P2RX7 blockade in vivo ameliorated neuropathic pain but also compromised production of CD8 + memory T cells. These findings show that activation of P2RX7 by eATP provides a common currency that both alerts the nervous and immune system to tissue damage, and promotes the metabolic fitness and survival of the most durable and functionally relevant memory CD8 + T cell populations. Activation of P2RX7 receptors by extracellular ATP is required for the generation, maintenance and function of central and tissue-resident CD8 + memory T cells.