P2X7 purinergic receptor plays a critical role in maintaining T-cell homeostasis and preventing lupus pathogenesis

The severe lymphoproliferative and lupus diseases developed by MRL/lpr mice depend on interactions between the Fas(lpr) mutation and MRL genetic background. Thus, the Fas(lpr) mutation causes limited disease in C57BL/6 mice. We previously found that accumulating B220(+) CD4(-)CD8(-) double negative (DN) T cells in MRL/lpr mice show defective P2X7 receptor ( P2X7)-induced cellular functions, suggesting that P2X7 contributes to T-cell homeostasis, along with Fas. Therefore, we generated a B6/lpr mouse strain (called B6/lpr-p2x7KO) carrying homozygous P2X7 knockout alleles. B6/lpr-p2x7KO mice accumulated high numbers of FasL-expressing B220(+) DN T cells of CD45RB(high)CD44(high) effector/memory CD8(+) T-cell origin and developed severe lupus, characterized by leukocyte infiltration into the tissues, high levels of IgG anti-dsDNA and rheumatoid factor autoantibodies, and marked cytokine network dysregulation. B6/lpr-p2x7KO mice also exhibited a considerably reduced lifespan. P2X7 is therefore a novel regulator of T-cell homeostasis, of which cooperation with Fas is critical to prevent lymphoaccumulation and autoimmunity.

Automated summary

The development of lymphoproliferative and lupus diseases in MRL/lpr mice depends on the interaction between the Fas(lpr) mutation and MRL genetic background. P2X7 receptor defect leads to abnormal accumulation of B220(+) CD4(-)CD8(-) double negative T cells in MRL/lpr mice, and the cooperation between P2X7 and Fas is critical for T-cell homeostasis.