Loss of P2X7 receptor membrane expression in B220+ double-negative T lymphocytes of autoimmune MRL/lpr mice (143.32)

Abstract

Abstract Lupus is an autoimmune disease influenced by multiple genetic loci. Fas-deficient MRL/lpr mice exhibit lupus and lymphoproliferative syndromes with massive accumulation of B220+CD4-CD8- (DN) T lymphocytes. Pathogenic B220+ DN T lymphocytes are derived from normal activated T lymphocytes which have not undergone activation-induced cell death due to inactivation of Fas. Normal activated peripheral T lymphocytes up-regulate the membrane phosphatase B220 before undergoing apoptosis. In Fas-deficient mice, activated T cells down-regulate CD4 or CD8 molecules but retain the expression of B220. P2X7R is an extracellular ATP-gated cell membrane receptor involved in the release of inflammatory cytokines and cell death. We show herein that MRL/lpr mice carry a P2X7R allele, which confers a high sensitivity to ATP. However, during aging, the MRL/lpr T-cell population exhibits a drastically reduced sensitivity to ATP-mediated stimulation of P2X7R. This decrease in P2X7R activity parallels the increase in B220+ DN T-cell numbers in lymphoid organs. The rare B220+ T cells observed in normal mice are also resistant to ATP treatment. Moreover, B cells, which express B220 as a developmental marker, are also dramatically less sensitive to ATP treatment. Using rabbit anti-P2X7R sera, we found a strong reduction in P2X7R levels on B220+ cells. Our results prompt the conclusion that B220 expression strongly correlates with the negative regulation of ATP/P2X7R pathway on both T and B cells.