ATP receptor P2rX7 direct the generation of long-lived memory CD8+ T cells

Abstract

Abstract P2rX7 is an ATP-sensitive purinergic receptor often known for its role in neuropathic pain and innate immunity. P2rX7 is also known to mediate CD4+ T cell death upon stimulation. To evaluate whether CD8+ T cell immune responses are also regulated by P2rX7, we infected mice with LCMV and tracked gp33-specific P14 CD8+ T cells. Unexpectedly, we found that P2rX7 expression on memory precursors (MPEC) positively correlated with generation of central memory CD8+ T cells (TCM). P2rX7KO CD8+ T cells also had reduced memory generation, especially TCM and resident memory (TRM). This defect was cell-intrinsic, as revealed by bone marrow chimeras and co-adoptive transfer of P2rX7KO and WT P14 T cells. Defective memory generation by P2rX7KO CD8+ T cells was preceded by impaired MPEC generation as well as diminished Tcf1 expression. Strikingly, P2rX7KO CD8+ T cells had an early and sustained impairment of proper mitochondrial function, as observed by flow cytometry (lower membrane potential and mitochondrial mass) or seahorse assays (lower SRC, higher proton leak). These defects were observed specifically on TCM, but not on effector memory (TEM) or long-lived effector cells (LLEC). P2rX7KO CD8+ T cells also showed reduced recall proliferation following secondary antigen stimulation. Importantly, treatment with P2rX7 pharmacological inhibitors during the immune response effector phase lead to similar defects in TCM and TRM. These findings show that P2rX7 is critical for development of a long-lived memory CD8+ T cell response. Also, they have important implications for the immunological effects of P2rX7 inhibitors used for pain control, and the impact of loss-of-function P2rX7 polymorphisms on immunity and the response to vaccines.