Characterizing modulation of CD8+ T cell homeostasis via extracellular damage sensors ARTC2.2 and P2RX7 4840

Description The NAD+-responsive, ADP-ribosyltransferase ARTC2.2 and the ATP-dependent ion channel P2RX7 represent two members of a pathway which controls T cell homeostasis in mice. Moderate P2RX7 activity supports development and maintenance of long-lived central and tissue-resident memory CD8+ T cells in humans and mice. However, covalent ADP-ribosylation of P2RX7 by ARTC2.2 in response to NAD+, released by tissue injury, enhances persistent, non-selective “macropore” formation by P2RX7, causing membrane depolarization and cell death. Amongst cells with high ARTC2.2 and P2RX7 expression, this sensitivity to NAD+ has led to methodologic difficulties characterizing immune responses in murine models and concerns for translatability to humans. Our objective was to assess the cell-intrinsic contribution of ARTC2.2 to CD8+ T cell homeostasis utilizing a novel ARTC2.2 deficient mouse and to test the central hypothesis that ARTC2.2 modulates pro-apoptotic capabilities of P2RX7 to regulate memory T cell survival. ARTC2.2 KO T cells activate P2RX7 ex vivo via ATP, but not with NAD+. After adoptive co-transfer and LCMV infection, recovery of ARTC2.2 KO CD8+ T cells yields greater viable memory T cells from lymphoid and non-lymphoid tissues, especially those with more processing post-extraction. Our results show ARTC2.2 negatively regulates the survival of memory T cells in response to local tissue injury via P2RX7 and in its absence allows better recovery and study of resident CD8+ T cells. Funding Sources This research was funded by NIH NHLBI T32 HL07741; NIH NCI F30 CA250321.