T RM maintenance is regulated by tissue damage via P2RX7 .

Tissue-resident memory T cells (T _RM ) 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 _RM to tissue damage. This history of danger-signal exposure is an important aspect of T _RM -mediated immunity that has been overlooked so far. RNA profiling revealed that T _RM 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 _RM but not in circulating T cells (T _CIRC ) 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 _RM P2RX7 activation in vivo by exogenous NAD ⁺ led to a specific depletion of T _RM while retaining T _CIRC The effect was absent in P2RX7-deficient mice and after P2RX7 blockade. TCR triggering down-regulated P2RX7 expression and made T _RM 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 _RM 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 _RM maintenance. Extracellular nucleotides released during infection and tissue damage could deplete T _RM 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 _RM in the tissue niche.
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