Unravelling immunoregulatory circuits of T cells

由于我们对调节组织免疫和直接炎症与免疫细胞调节功能的因素感兴趣，我们研究了T细胞进入组织部位时诱导的基因。我们在人类的RNA测序中观察到，迁移到肺组织中的免疫细胞，诱导程度最高的途径之一是补体途径，而补体因子3（C3）是诱导程度最高的基因之一。我们使用报告者证实了这些发现，并继续表明内皮细胞（ICAM-1）上的同源配体与细胞受体（LFA 1）的结合诱导了导致C3转录的转录信号（AP-1）。我们继续证实了C3表达在调节细胞代谢和免疫细胞执行炎症功能的“适应性”中的关键性。因此，来自表现为白细胞粘附疾病1（LAD-1）的LFA-1缺陷患者的T细胞具有炎症功能的内在缺陷，其可以通过恢复细胞内的C3表达而成比例地恢复。这项工作于2020年发表在Immunity上。 由于SARS冠状病毒（SARS-CoV 2）大流行，我们的主要工作已经减少，我们不得不转移重点，为我们对SARS-CoV 2的理解做出贡献。我们目前正在审查两份手稿，希望能在2021财年发表。这两份手稿的重点是肺组织中局部炎症的调节主要是由局部产生的因素。

Because of our interest in the factors that regulate tissue immunity and direct inflammatory versus regulatory functions of immune cells, we studied the genes induced in T cells as they enter a tissue site. We observed in RNA-seq of humans that immune cells that had migrated into lung tissues that one of the most highly induced pathways was the complement pathway and that complement factor 3 (C3) was one of the most highly induced genes. Using a reporter we confirmed these findings and went on to show that engagement of cell receptor receptors (LFA1) by cognate ligands on endothelial cells (ICAM-1) induced a transcriptional signal (AP-1) that led to transcription of C3. We went on to confirm the criticality of C3 expression in regulating cellular metabolism and "fitness" of immune cells to carry out inflammatory functions. Accordingly, T cells from patients with deficiency in LFA-1 manifesting as leukocyte adhesion disease 1 (LAD-1) had intrinsic defects in inflammatory function that could be restored proportionally by restoration of C3 expression inside the cells. This work was published in Immunity in 2020. Due to the SARS-Coronavirus (SARS-CoV2) pandemic, our primary efforts have been curtailed and we have had to switch focus to make contributions to our understanding of SARS-CoV2. We have two manuscripts currently under review, which will hopefully result in publications in FY21. The focus of both manuscripts is the regulation of local inflammation in lung tissues by factors primarily produced locally.