P2X7 receptor signaling is not required but can enhance Th17 differentiation.

Abstract

The purinergic receptor P2X7 (P2X7R) is important in inflammasome activation and generally considered to favor proinflammatory Th17 immune responses. However, several studies utilizing P2rx7-/- mice did not observe impaired inflammation, on the contrary, these reports demonstrate that P2rx7-/- mice can have more sever inflammation compared to WT controls. To begin to clarify this discrepancy, the impact of P2X7R signaling on primary Th17 and Th1 cell responses was examined. Initially, utilizing a global knockout approach, we found that P2rx7-/- mice develop comparable Th17 and Th1 responses to those of WT mice. However, indepth in vitro and in vivo investigations revealed differences in the immune response outcome depending on which cell type expresses P2X7R. In this regard, DC-specific P2X7R deficient chimeras demonstrate a comparable Th17 differentiation pattern with that of WT chimeras but display a significantly enhanced Th1 response. However, P2rx7-/- T cells have a suppressed Th17 differentiation profile while developing a similarly enhanced Th1 response as observed in DC-specific P2X7R deficient chimeras. Finally, P2X7R expression induces more T cell death in vivo, attributed to its cytotoxicity, which results in a similar total number of WT Th17 and P2rx7-/- Th17 cells and remarkably higher amounts of P2rx7-/- Th1 cells. Collectively, our findings establish that P2X7R expression on CD4+ T cells is necessary for Th17 differentiation while inhibiting Th1 development.