Abstract

It has been hypothesized that type 1 diabetes is initiated by neonatal physiological pancreatic β-cell death, indicating that the early stages of this autoimmune response may reflect a dysregulated response to immune “danger” signals. One potential danger signal is ATP, high concentrations of which stimulate the purinergic receptor P2X₇ on hematopoietic cells. We compared the sensitivity of lymphocytes from model type 1 diabetic (NOD) and control (C57BL/10) mice to activation of this pathway. Stimulation of the P2X₇ receptor of NOD mice resulted in more pronounced shedding of the lymphocyte homing receptor CD62L and in increased programmed cell death. Levels of major histocompatibility complex class I molecules, which have previously been reported to be poorly expressed on NOD lymphocytes, were initially normal, but the molecules were shed preferentially from NOD cells after P2X₇ receptor stimulation. Thus, although NOD lymphocytes have been considered resistant to programmed cell death, they are highly sensitive to that stimulated through the P2X₇ receptor. Because NOD mice express a low activation threshold allele of the P2X₇ receptor and the P2X₇ gene maps to a locus associated with disease, P2X₇ is a good candidate susceptibility gene for NOD diabetes.