Purinergic P2X7 receptor in type 1 diabetes
Research area: Mucosal Immunology
Group leaders: Fabio Grassi
Status: In progress
Although P2rx7 has been proposed as a type 1 diabetes (T1D) susceptibility gene in non-obese diabetic (NOD) mice, its potential pathogenic role has not been directly determined. To test this possibility we investigated P2rx7 expression in CD4+CD62LhighCD44low naive and CD4+CD62LlowCD44high effector from pancreatic lymph nodes of healthy, prediabetic and overtly diabetic NOD mice. P2rx7 expression significantly increases in CD4+ T effector cells of prediabetic NOD mice but dramatically decreases in NOD mice with overt disease. Since P2rx7 is silenced by cognate antigen stimulation these observations underscore the relevance of pancreatic epitope spreading in the development of T1D in NOD mice. Downregulation of P2rx7 would render effector T cells resistant to pyroptosis induction by extracellular ATP generated by inflammatory tissue damage, thereby propagating and sustaining tissue destruction. The role of P2X7 activity in limiting the T cell diabetogenic potential was supported by T1D induction with low-dose of streptozotocin in P2rx7 knock-out mice, which developed a significantly more severe disease than the wild-type counterpart.