Unravelling immunoregulatory circuits of tissue inflammation

在过去的几年里，我们已经证明细胞自主补体是由免疫和非免疫细胞产生的，并描述了它们诱导的主要途径，特别是T细胞中LFA诱导的信号和呼吸道上皮细胞中的I型干扰素。这些发现很重要，因为它们表明，无法获得血浆循环补体的炎症组织实际上代表了补体丰富的环境，这里的补体既来自免疫细胞，也来自非细胞。 因此，我们假设，研究补体激活的T细胞的转录将揭示补体对T细胞的影响。我们发现补体在T细胞中诱导自分泌/旁分泌维生素D(VitD)系统，这是适当的炎性T细胞关闭所必需的，从而允许组织愈合发生。简而言之，我们发现补体诱导了一个细胞固有的VitD系统，允许T细胞激活并对VitD做出反应。对活性维生素D的感知引起了全基因组的表观遗传学变化，这些变化产生了新的和扩大了现有的超级增强子，并招募了关键的转录因子(主要是VDR、c-jun、STAT3和BACH2)，从而在T细胞中形成了维生素D反应。我们发现，正如我们以前所做的那样，BACH2在这些事件中是一个中心因子。新冠肺炎患者的T细胞显示Th1型细胞过度活化，并存在维生素D关闭程序的异常调节，提示缺乏底物(维生素D缺乏)和/或该系统调节异常。这些数据可能解释了维生素D不足/缺乏与患新冠肺炎和感染后死亡的风险之间的流行病学联系。它们也值得注意，因为它们在我们实验室的两个主要利益集团--补充剂和TF BACH2之间建立了交叉监管。我们发现，这个系统在银屑病患者的皮肤上是有效的，并且在约伯和布里达综合征患者的细胞中调节失调。 作为与英国同事合作的一部分，我们还表明，激活的维生素D抑制效应细胞CD4+T细胞的糖酵解程序，从而抑制炎症功能。这篇论文发表在《免疫学》杂志上。 最后，通过分别与Portilla和Lionakis实验室的合作，我们还证明了补体C5系统也是激活肾脏中髓系细胞的关键，这种细胞导致了急性肾损伤后的组织瘢痕形成(叶酸模型)，并且C5对于抗真菌免疫是必不可少的。因此，C5在人类和小鼠中的拮抗作用易于发生侵袭性真菌疾病。这些患者分别发表在《美国生理学杂志》上，目前正在接受审查。

In the past years we had shown that cell-autonomous Complement is produced both from immune and non-immune cells and delineated the major pathways of their induction, notably LFA-induced signals in T cells and type I interferons in respiratory epithelial cells. These findings were important because they indicated that inflamed tissues, which are unable to access plasma-circulating complement, actually represent a complement-rich environment, the complement here being derived from both immune and non-cells. We thus hypothesized that studying transcriptomes of Complement-activated T cells would reveal the effects of Complement on T cells. We showed that Complement induces a self-contained autocrine/paracrine vitamin D (VitD) system in T cells that is required for appropriate inflammatory T cell shut-down, permitting tissue healing to take place. Briefly, we found that Complement induced a cell-intrinsic VitD system permitting T cells to both activate and respond to VitD. Sensing of active VitD caused genome-wide epigenetic changes that generated new and augmented existing super-enhancers, and recruited key TFs (principally VDR, c-JUN, STAT3 and BACH2) that shaped the VitD response in T cells. We found, as we had done before, that BACH2 was a central TF in these events. T cells of patients with COVID-19 showed Th1 hyper-activation and evidence of dysregulation of this VitD shut-down program, indicating either a lack of substrate (VitD deficiency) and/or abnormal regulation of this system. These data may explain the epidemiologic link between vitamin D insufficiency/deficiency and risk of both developing COVID-19 and suffering mortality after infection. They are also noteworthy because they establish cross-regulation between the two main interests of our lab, Complement and the TF BACH2. We found that this system was operational in psoriatic skin and dysregulated in cells from patients with Job and BRIDA syndromes. As part of a collaboration with colleagues in the UK we also showed that activated Vitamin D represses glycolytic programs in effector CD4+ T cells to repress inflammatory functions. This paper was published in Immunology. Finally, through a collaboration with the Portilla and Lionakis labs, respectively, we also demonstrated that the Complement C5 system is also key to activation of myeloid cells in the kidneys that drive tissue scarring following acute kidney injury (the folic acid model) and that C5 is essential for anti-fungal immunity. Thus, C5 antagonism in humans and mice predisposes to invasive fungal diseases. These patients were published in the American Journal of Physiology and are under review, respectively.