Unravelling immunoregulatory circuits of T cells

在本财政年度，我们进行了以下研究观察，这些观察已经过同行评审并发表： 1.我们使用深度表型分析方法来寻找具有独特特性的抗炎免疫细胞（调节性T细胞）群体。我们发现了一个这样的群体，它具有高度的抗炎特性，但也产生了通常仅限于炎症免疫细胞的可溶性因子。通过利用最先进的基因组询问方法，我们确定了这些细胞的独特特性是如何被调节的，以及它们产生的可溶性因子加速了伤口愈合。我们发现它们在肠道中富集，并且它们似乎对炎症性肠病有益。这些特性表明，这些细胞可能有利于基于细胞的治疗方案，用于治疗人类炎症性肠病。这项工作发表在Nature Immunology上。 2.我们对组织中产生的因子如何影响T细胞生物学有着浓厚的兴趣，因为这些因子与T细胞到达炎症部位（如肾脏）时的行为特别相关。与肾脏相关的关键系统之一是补体系统。今年，我们与NHLBI的一位主要合作者一起确定，CD 8细胞上的补体受体参与是这些细胞对抗病毒感染的最佳功能的必要条件。这些信号改变了CD 8细胞中的脂肪酸代谢，这是值得注意的，因为人们越来越认识到改变细胞的代谢功能是调节免疫细胞的关键手段。这项工作发表在Nature Communications上。我们随后在《免疫学进展》上发表了一篇综述文章，详细介绍了补体系统调节T细胞行为的一些方法。 3.抗炎性T细胞中的一种重要转录因子称为STAT 5。与NIAID的同事一起，我们参与描述了STAT 5信号在小鼠和人类炎症类型T细胞死亡中的意想不到的作用。作为其中的一部分，我们描述了一个独特的患者与杂合错义突变的卷曲螺旋结构域的STAT 5 B，提出了自身免疫性淋巴增生综合征样的功能。蛋白质突变对基因的正常拷贝具有显性负效应，从而导致疾病，尽管患者只有一个异常基因拷贝。这篇论文发表在Journal of Immunology上。 4.因为我们使用最先进的基因组询问方法，所以我们的团队处于数据分析和整合的计算方法的最前沿是很重要的。为此，我们与普渡大学的Kazemian教授进行了长期合作，他经营着一个干（计算）和湿实验室。我们一直在研究在测序数据中询问暗物质的方法。这些数据主要是来自感染细胞的病毒的测序信息，但通常被忽略，因为它们没有“映射”到人类基因组。通过特别关注这些信息并利用来自>1000个RNA测序数据集的这些数据，我们对人类EB病毒感染进行了一些新的观察，这是淋巴恶性肿瘤的主要原因。建立了一个全面的宿主-病原体相互作用组图谱，并对病毒对宿主细胞的作用进行了一些有趣的观察，反之亦然。这项工作可能有助于为EBV相关癌症患者选择个性化治疗，并发表在《癌症研究》上。

In this fiscal year we made the following research observations that have been peer reviewed and published: 1. We used deep phenotyping methods to look for populations of anti-inflammatory immune cells (regulatory T cells) with unique properties. We found one such population that that highly anti-inflammatory properties but that also produced soluble factors normally restricted to inflammatory immune cells. By leveraging state of the art genome interrogation methods we identified how the unique properties of these cells were regulated and that the soluble factors they produced accelerated wound healing. We found them to be enriched in the gut and that they appeared to be beneficial in inflammatory bowel disease. These properties suggest that these cells may be beneficial in programs of cell-based therapy for the treatment of inflammatory bowel disease in humans. This work was published in Nature Immunology. 2. We have a strong interest in how how factors produced in tissues affect T cell biology, since these are particularly relevant to what T cells do when they reach sites of inflammation, such as the kidneys. One of the key kidney-relevant systems is the complement system. Together with one of our main collaborators in NHLBI we established this year that complement receptor engagement on CD8 cells is a requirement for optimal function of these cells for fighting viral infections. Such signals altered fatty acid metabolism in CD8 cells, which is of note because it is being increasingly recognized that altering metabolic function of cells is a key means by which immune cells are regulated. This work was published in Nature Communications. We followed this up with a review article in Advances in Immunology detailing some of the means by which the complement system regulates T cell behavior. 3. An essential transcription factor in anti-inflammatory T cells is called STAT5. Together with colleagues in NIAID we were involved in the description of an unexpected role of STAT5 signaling in the death of inflammatory types of T cells in both mice and humans. As part of this, we described a unique patient with a heterozygous missense mutation in the coiled-coil domain of STAT5B that presented with autoimmune lymphoproliferative syndrome-like features. The protein mutation had a dominant negative effect over the normal copy of the gene, thus causing disease despite the patient having only one abnormal gene copy. This paper was published in the Journal of Immunology. 4. Because we use cutting edge genome interrogation methods, it is important for our group to be at the forefront of computational methods for data analysis and integration. For this purpose we have a long-term collaboration with Prof Kazemian at Purdue university, who runs a dry (computational) and wet lab. We have been working on methodology for interrogation of dark matter in sequencing data. Such data is mostly sequenced information from viruses that have infected cells, but that are normally ignored because they do not "map" to the human genome. By focussing specifically on this information and leveraging such data from >1000 RNA sequencing data sets, we made some novel observations about Epstein-Barr virus infections in humans, which is a major cause of lymphoid malignancies. A comprehensive host-pathogen interactome map was created and some interesting observations regarding what the virus does to host cells and vice versa were made. This work could help in the selection of individualized therapies for patients with EBV-associated cancers and was published in Cancer Research.