T maintenance is regulated by tissue damage via P2RX7

Area of Science:

• Immunology
• Cell Biology
• Tissue Engineering

Background:

• Tissue-resident memory T cells (T_RM) provide local immunity but face tissue damage.
• The role of danger signals in T_RM homeostasis is poorly understood.

Purpose of the Study:

• To investigate the role of P2RX7 receptor in T_RM cell regulation and survival.
• To understand how tissue damage impacts T_RM cell populations.

Main Methods:

• RNA profiling of T_RM cells from liver and small intestine.
• P2RX7 expression analysis in T_RM and circulating T cells (T_CIRC).
• In vivo and in vitro experiments using NAD⁺, P2RX7 blockade, and acetaminophen-induced liver injury models.

Main Results:

• T_RM cells express P2RX7, a receptor for extracellular nucleotides like ATP and NAD⁺.
• P2RX7 activation by tissue damage or exogenous NAD⁺ selectively depletes T_RM cells.
• TCR triggering reduces P2RX7 expression, conferring resistance to NAD-induced cell death.

Conclusions:

• P2RX7 signaling is crucial for regulating T_RM cell maintenance.
• Tissue damage-induced nucleotide release can deplete local T_RM cells, creating niches for new immune specificities.
• Recognition of tissue damage favors antigen-specific T_RM persistence over bystander cells.