Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system.
Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system.
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DOI：
10.1038/nature19334
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发表时间：
2016-09-08
期刊：
影响因子：
64.8
通讯作者：
Boothby, Mark R.
中科院分区：
文献类型：
--
作者：
Cho, Sung Hoon;Raybuck, Ariel L.;Stengel, Kristy;Wei, Mei;Beck, Thomas C.;Volanakis, Emmanuel;Thomas, James W.;Hiebert, Scott;Haase, Volker H.;Boothby, Mark R.
老年保健中心促进体液免疫和疫苗效力。在GC中，抗原活化的B细胞增殖，表达高亲和力抗体，促进抗体类别转换，并产生B细胞记忆。尽管细胞因子环境长期以来已知调节效应子功能，包括免疫球蛋白类别的选择，细胞自主的和外在的，代谢编程已经成为T细胞介导的免疫的调节剂。在这里，我们表明，在小鼠GC轻区缺氧，低氧张力（）改变B细胞的生理和功能。除增殖减少和B细胞死亡增加外，低通过限制活化诱导的胞嘧啶脱氨酶（AID）的表达损害抗体类别向促炎性IgG 2c抗体同种型的转换。缺氧通过限制脯氨酰羟基双加氧酶的活性来诱导HIF转录因子，脯氨酰羟基双加氧酶通过结合von Hippel-Landau肿瘤抑制蛋白（pVHL）来羟基化HIF-1α和HIF-2α以使HIF不稳定。pVHL的B细胞特异性消耗导致组成性HIF稳定化，减少抗原特异性GC B细胞并破坏高亲和力IgG的产生，转换为IgG 2c，早期记忆B细胞和回忆抗体应答。HIF诱导可以重编程代谢和生长因子基因表达。pVHL缺陷导致的持续缺氧或HIF诱导抑制了B淋巴母细胞中mTOR复合物1（mTORC 1）的活性，mTORC 1单倍缺陷型B细胞的克隆扩增、AID表达和产生IgG 2c和高亲和力抗体的能力降低。因此，GC的正常生理学涉及缺氧的区域性变化，并且HIF依赖性氧传感调节B细胞的生命功能。我们认为，淋巴器官中的氧的限制，这可以改变病理生理状态，调节体液免疫。
Germinal centres (GCs) promote humoral immunity and vaccine efficacy. In GCs, antigen-activated B cells proliferate, express high-affinity antibodies, promote antibody class switching, and yield B cell memory,. Whereas the cytokine milieu has long been known to regulate effector functions that include the choice of immunoglobulin class,, both cell-autonomous and extrinsic, metabolic programming have emerged as modulators of T-cell-mediated immunity. Here we show in mice that GC light zones are hypoxic, and that low oxygen tension () alters B cell physiology and function. In addition to reduced proliferation and increased B cell death, low impairs antibody class switching to the pro-inflammatory IgG2c antibody isotype by limiting the expression of activation-induced cytosine deaminase (AID). Hypoxia induces HIF transcription factors by restricting the activity of prolyl hydroxyl dioxygenase enzymes, which hydroxylate HIF-1α and HIF-2α to destabilize HIF by binding the von Hippel–Landau tumour suppressor protein (pVHL). B-cell-specific depletion of pVHL leads to constitutive HIF stabilization, decreases antigen-specific GC B cells and undermines the generation of high-affinity IgG, switching to IgG2c, early memory B cells, and recall antibody responses. HIF induction can reprogram metabolic and growth factor gene expression. Sustained hypoxia or HIF induction by pVHL deficiency inhibits mTOR complex 1 (mTORC1) activity in B lymphoblasts, and mTORC1-haploinsufficient B cells have reduced clonal expansion, AID expression, and capacities to yield IgG2c and high-affinity antibodies. Thus, the normal physiology of GCs involves regional variegation of hypoxia, and HIF-dependent oxygen sensing regulates vital functions of B cells. We propose that the restriction of oxygen in lymphoid organs, which can be altered in pathophysiological states, modulates humoral immunity.
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