Program for Inflammatory and Cardiovascular Disorders, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, 08003, Spain.
Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Nat Commun. 2017 Nov 13;8(1):1462. doi: 10.1038/s41467-017-01602-4.
Mechanistic target of rapamycin (mTOR) enhances immunity in addition to orchestrating metabolism. Here we show that mTOR coordinates immunometabolic reconfiguration of marginal zone (MZ) B cells, a pre-activated lymphocyte subset that mounts antibody responses to T-cell-independent antigens through a Toll-like receptor (TLR)-amplified pathway involving transmembrane activator and CAML interactor (TACI). This receptor interacts with mTOR via the TLR adapter MyD88. The resulting mTOR activation instigates MZ B-cell proliferation, immunoglobulin G (IgG) class switching, and plasmablast differentiation through a rapamycin-sensitive pathway that integrates metabolic and antibody-inducing transcription programs, including NF-κB. Disruption of TACI-mTOR interaction by rapamycin, truncation of the MyD88-binding domain of TACI, or B-cell-conditional mTOR deficiency interrupts TACI signaling via NF-κB and cooperation with TLRs, thereby hampering IgG production to T-cell-independent antigens but not B-cell survival. Thus, mTOR drives innate-like antibody responses by linking proximal TACI signaling events with distal immunometabolic transcription programs.
雷帕霉素靶蛋白（mTOR）除了调节代谢外，还增强免疫。在这里，我们表明 mTOR 协调边缘区（MZ）B 细胞的免疫代谢重新配置，MZ B 细胞是一种预先激活的淋巴细胞亚群，通过涉及跨膜激活剂和钙调蛋白相互作用因子（TACI）的 Toll 样受体（TLR）放大途径对 T 细胞非依赖性抗原产生抗体反应。该受体通过 TLR 衔接蛋白 MyD88 与 mTOR 相互作用。由此产生的 mTOR 激活通过雷帕霉素敏感途径引发 MZ B 细胞增殖、免疫球蛋白 G（IgG）类别转换和浆母细胞分化，该途径整合代谢和诱导抗体的转录程序，包括 NF-κB。雷帕霉素破坏 TACI-mTOR 相互作用、TACI 结合 MyD88 结构域的截断或 B 细胞条件性 mTOR 缺乏通过 NF-κB 中断 TACI 信号转导并与 TLR 合作，从而阻碍 T 细胞非依赖性抗原的 IgG 产生，但不影响 B 细胞存活。因此，mTOR 通过将近端 TACI 信号事件与远端免疫代谢转录程序联系起来，驱动先天样抗体反应。
