Activated Human CD4+CD45RO+ Memory T-Cells Indirectly Inhibit NLRP3 Inflammasome Activation through Downregulation of P2X7R Signalling

Inflammasomes are multi-protein complexes that control the production of pro-inflammatory cytokines such as IL-1β. Inflammasomes play an important role in the control of immunity to tumors and infections, and also in autoimmune diseases, but the mechanisms controlling the activation of human inflammasomes are largely unknown. We found that human activated CD4+CD45RO+ memory T-cells specifically suppress P2X7R-mediated NLRP3 inflammasome activation, without affecting P2X7R-independent NLRP3 or NLRP1 inflammasome activation. The concomitant increase in pro-IL-1β production induced by activated memory T-cells concealed this effect. Priming with IFNβ decreased pro-IL-1β production in addition to NLRP3 inflammasome inhibition and thus unmasked the inhibitory effect on NLRP3 inflammasome activation. IFNβ suppresses NLRP3 inflammasome activation through an indirect mechanism involving decreased P2X7R signaling. The inhibition of pro-IL-1β production and suppression of NLRP3 inflammasome activation by IFNβ-primed human CD4+CD45RO+ memory T-cells is partly mediated by soluble FasL and is associated with down-regulated P2X7R mRNA expression and reduced response to ATP in monocytes. CD4+CD45RO+ memory T-cells from multiple sclerosis (MS) patients showed a reduced ability to suppress NLRP3 inflammasome activation, however their suppressive ability was recovered following in vivo treatment with IFNβ. Thus, our data demonstrate that human P2X7R-mediated NLRP3 inflammasome activation is regulated by activated CD4+CD45RO+ memory T cells, and provide new information on the mechanisms mediating the therapeutic effects of IFNβ in MS.

炎性体（Inflammasomes）是一类调控促炎细胞因子（如白细胞介素1β，IL-1β）生成的多蛋白复合物。炎性体在抗肿瘤、抗感染免疫调控以及自身免疫病的发生发展中发挥重要作用，但目前人类炎性体的激活调控机制仍未被完全阐明。本研究发现，活化的CD4+CD45RO+记忆T细胞（CD4+CD45RO+ memory T-cells）可特异性抑制P2X嘌呤受体7（P2X7R）介导的NLRP3炎性体（NLRP3 inflammasome）激活，而不影响不依赖P2X7R的NLRP3或NLRP1炎性体（NLRP1 inflammasome）激活。活化的记忆T细胞诱导的前体白细胞介素1β（pro-IL-1β）生成增加会掩盖这一抑制效应。经干扰素β（IFNβ）预刺激不仅可抑制NLRP3炎性体激活，还可降低pro-IL-1β的生成，从而暴露了其对NLRP3炎性体激活的抑制作用。IFNβ通过一种间接机制抑制NLRP3炎性体激活，该机制涉及P2X7R信号通路的减弱。经IFNβ预刺激的人类CD4+CD45RO+记忆T细胞对pro-IL-1β生成的抑制以及对NLRP3炎性体激活的调控，部分由可溶性Fas配体（soluble FasL）介导，且与单核细胞中P2X7R mRNA表达下调、ATP应答反应减弱相关。多发性硬化症（MS）患者来源的CD4+CD45RO+记忆T细胞，其抑制NLRP3炎性体激活的能力有所减弱，但经体内IFNβ治疗后，这种抑制功能可得到恢复。综上，本研究数据证实，人类P2X7R介导的NLRP3炎性体激活可被活化的CD4+CD45RO+记忆T细胞调控，并为阐明IFNβ治疗多发性硬化症的作用机制提供了新的见解。