T RM maintenance is regulated by tissue damage via P2RX7

• Published in: Science immunology 2018-12, Vol.3 (30)
• Main Authors: Stark, Regina, Wesselink, Thomas H, Behr, Felix M, Kragten, Natasja A M, Arens, Ramon, Koch-Nolte, Friedrich, van Gisbergen, Klaas P J M, van Lier, René A W
• Format: Article
• Language: English
• ISSN: 2470-9468; 2470-9468
• DOI: 10.1126/sciimmunol.aau1022

Tissue-resident memory T cells (T ) are noncirculating immune cells that contribute to the first line of local defense against reinfections. Their location at hotspots of pathogen encounter frequently exposes T to tissue damage. This history of danger-signal exposure is an important aspect of T -mediated immunity that has been overlooked so far. RNA profiling revealed that T 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 T but not in circulating T cells (T ) across different infection models. Tissue damage induced during routine isolation of liver lymphocytes led to P2RX7 activation and resulted in selective cell death of T P2RX7 activation in vivo by exogenous NAD led to a specific depletion of T while retaining T The effect was absent in P2RX7-deficient mice and after P2RX7 blockade. TCR triggering down-regulated P2RX7 expression and made T 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 T in wild-type but not in P2RX7 KO T cells. Our results highlight P2RX7-mediated signaling as a critical pathway for the regulation of T maintenance. Extracellular nucleotides released during infection and tissue damage could deplete T 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 T in the tissue niche.