AUTHOR=Mellouk Amine , Hutteau-Hamel Tom , Legrand Julie , Safya Hanaa , Benbijja Mohcine , Mercier-Nomé Françoise , Benihoud Karim , Kanellopoulos Jean M. , Bobé Pierre 

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

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.957008

DOI=10.3389/fimmu.2022.957008

ISSN=1664-3224

ABSTRACT=<p>The severe lymphoproliferative and lupus diseases developed by MRL/<italic>lpr</italic> mice depend on interactions between the Fas<sup><italic>lpr</italic></sup> mutation and MRL genetic background. Thus, the Fas<sup><italic>lpr</italic></sup> mutation causes limited disease in C57BL/6 mice. We previously found that accumulating B220<sup>+</sup> CD4<sup>–</sup>CD8<sup>–</sup> double negative (DN) T cells in MRL/<italic>lpr</italic> 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/<italic>lpr</italic> mouse strain (called B6/<italic>lpr</italic>-<italic>p2x7</italic>KO) carrying homozygous P2X7 knockout alleles. B6/<italic>lpr</italic>-<italic>p2x7</italic>KO mice accumulated high numbers of FasL-expressing B220<sup>+</sup> DN T cells of CD45RB<sup>high</sup>CD44<sup>high</sup> effector/memory CD8<sup>+</sup> 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/<italic>lpr</italic>-<italic>p2x7</italic>KO 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.</p>