Research ArticleT CELL MEMORY

TRM maintenance is regulated by tissue damage via P2RX7

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Science Immunology  14 Dec 2018:
Vol. 3, Issue 30, eaau1022
DOI: 10.1126/sciimmunol.aau1022

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Tissue damage triggers a TRM trim down

Noncirculating tissue-resident memory T cells (TRM) provide rapid host defense after reexposure to a previously encountered pathogen. Stark et al. found that TRM in the liver and small intestine expressed high levels of the P2RX7 purinergic receptor compared with circulating T cells. Release of extracellular nucleotides that are P2RX7 ligands (ATP and NAD+) in a mouse model of sterile liver injury selectively enhanced the death of liver TRM compared with circulating T cells, whereas concurrent TCR engagement promoted survival of TRM. These findings help define the signaling pathways that shape the clonal composition of the TRM compartment on an ongoing basis.

Abstract

Tissue-resident memory T cells (TRM) are noncirculating immune cells that contribute to the first line of local defense against reinfections. Their location at hotspots of pathogen encounter frequently exposes TRM to tissue damage. This history of danger-signal exposure is an important aspect of TRM-mediated immunity that has been overlooked so far. RNA profiling revealed that TRM from liver and small intestine express P2RX7, a damage/danger-associated molecular pattern (DAMP) receptor that is triggered by extracellular nucleotides (ATP, NAD+). We confirmed that P2RX7 protein was expressed in CD8+ TRM but not in circulating T cells (TCIRC) across different infection models. Tissue damage induced during routine isolation of liver lymphocytes led to P2RX7 activation and resulted in selective cell death of TRM. P2RX7 activation in vivo by exogenous NAD+ led to a specific depletion of TRM while retaining TCIRC. The effect was absent in P2RX7-deficient mice and after P2RX7 blockade. TCR triggering down-regulated P2RX7 expression and made TRM resistant to NAD-induced cell death. Physiological triggering of P2RX7 by sterile tissue damage during acetaminophen-induced liver injury led to a loss of previously acquired pathogen-specific local TRM in wild-type but not in P2RX7 KO T cells. Our results highlight P2RX7-mediated signaling as a critical pathway for the regulation of TRM maintenance. Extracellular nucleotides released during infection and tissue damage could deplete TRM locally and free niches for new and infection-relevant specificities. This suggests that the recognition of tissue damage promotes persistence of antigen-specific over bystander TRM in the tissue niche.

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