Rahman Jubayer, Bibby Jack A, Singh Parul, Merle Nicolas S, West Erin E, Bohrer Andrea, Mayer-Barber Katrin, Liu Chengyu, Brinster Lauren R, Afzali Behdad, Briones Ana M, Alehashemi Sara, Bhuyan Farzana, Ge Jiahui, Chen Xijian, Zhou Yingbi, Clarke Murray C H, Liu Bin, Goldbach-Mansky Raphaela, Serezani C Henrique, Kemper Claudia
Complement and Inflammation Research Section, NHLBI, NIH, Bethesda, MD 20892, USA.
Complement and Inflammation Research Section, NHLBI, NIH, Bethesda, MD 20892, USA.
Immunity. 2025 Jun 10;58(6):1438-1455.e10. doi: 10.1016/j.immuni.2025.05.003. Epub 2025 May 30.
T helper 1 (Th1) cell initiation pathways are well characterized; however, those regulating their contraction are less understood. Here, we define a CD4 T cell-autonomous pathway in which complement C5 orchestrated a shift from prostaglandin E2 (PGE2) dominance to enhanced prostacyclin (PGI2) production via activation of C5a receptor 2 (C5aR2). This pivot in lipid mediators induced autocrine signaling through the PGI2 receptor and expression of the interleukin-1 (IL-1) decoy IL-1 receptor type 2 (IL-1R2), which sequestered Th1 cell-driving intrinsic IL-1β, facilitating Th1 cell contraction. Disruption of this C5aR2-PGI2-R axis was a hallmark of pathologically persistent Th1 cell activity in inflammatory conditions, including cryopyrin-associated periodic syndromes (CAPS), Crohn's disease, and rheumatoid arthritis. Rebalancing this axis through selective PGE2 synthase inhibition rectified the hyperactive Th1 cell phenotype in vitro in T cells from individuals with CAPS. Therefore, complement is a key controller of prostanoid metabolism, and the latter is an intrinsic-and potentially druggable-checkpoint for the cessation of Th1 cell effector responses.
辅助性T细胞1（Th1）细胞的起始途径已得到充分表征；然而，对其调控收缩的途径了解较少。在这里，我们定义了一条CD4 T细胞自主途径，其中补体C5通过激活C5a受体2（C5aR2），协调了从前列腺素E2（PGE2）主导到前列环素（PGI2）生成增强的转变。这种脂质介质的转变通过PGI2受体诱导自分泌信号，并促使白细胞介素-1（IL-1）诱饵白细胞介素-1受体2型（IL-1R2）表达，该受体隔离了驱动Th1细胞的内源性IL-1β，促进了Th1细胞的收缩。在包括冷吡啉相关周期性综合征（CAPS）、克罗恩病和类风湿关节炎在内的炎症条件下，这种C5aR2-PGI2-R轴的破坏是病理性持续Th1细胞活性的标志。通过选择性抑制PGE2合酶来重新平衡该轴，可纠正CAPS患者T细胞在体外的过度活跃Th1细胞表型。因此，补体是前列腺素代谢的关键调控因子，而前列腺素代谢是Th1细胞效应反应终止的一个内在且可能可药物靶向的检查点。
