The Prostacyclin Receptor is a Nrf2-regulated Immune Checkpoint in CD8+ T cells

Understanding how circulating metabolites enforce pathways in dysfunctional immune cells may illuminate modes of intervention directed at reviving immune function. The NRF2 pathway is the most widely documented cytoprotective axis in land-dwelling eukaryotes. However, the role of this pathway in CD8+ T cells—which seek and destroy tumors and pathogen infected cells—has yet to be elucidated. Our lab has conducted a RNAseq meta-analysis of CD8+ T cells upon tumor, viral and bacterial inoculation. Curiously, the NRF2 pathway was robustly upregulated in dysfunctional CD8+T cells. To further investigate the role of NRF2 in these contexts we developed a mouse model whereby the NRF2 axis is permanently hyperactivated in CD8+ T cells, hereafter referred to as NRF2Hi. Our in vivo data demonstrate that NRF2Hi CD8+ T cells offer little overall cytoprotection and poorly control tumors and pathogens versus wildtype (WT) control CD8+ T cells. To understand why upregulation of the NRF2 axis could be unfavorable to CD8+ T cell function we conducted RNAseq on NRF2Hi versus WT cells upon viral infection of mice. We found that NRF2Hi cells massively upregulate the prostacyclin receptor (PTGIR), which binds to prostacyclin—a circulating metabolite of arachidonic acid that has only been investigated in vasodilation and is seemingly benign to CD8+ T cells. To decipher the role of PTGIR in CD8+ T cells, we silenced its expression and observed a revival of CD8+ T cell function, significantly reducing tumor and pathogen burden. Collectively, our data illuminate a NRF2-regulated immune checkpoint, PTGIR. Interventions that suppress the interaction between PTGIR and prostacyclin may serve therapeutic benefit in clinical contexts such as cancer and chronic pathogen infections. We adoptively transferred WT and KEAP1 KO (NRF2Hi) CD8 LCMV-specific (P14) CD90.1 cells into congenic CD90.2 hosts prior to infection with the acute, Armstrong strain of LCMV. On day 7 post infection, cells were isolated and RNAseq was performed. Data represent 5 mice total per condition, from 2 separate biological runs