Unravelling immunoregulatory circuits of T cells

由于我们对调节组织免疫和免疫细胞直接炎症和调节功能的因子感兴趣，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-SEQ中观察到，已经迁移到肺组织中的免疫细胞是最高诱导途径之一是补体途径，补体因子3(C3)是最高诱导基因之一。利用一名记者，我们证实了这些发现，并进一步表明，内皮细胞(ICAM-1)上的同源配体与细胞受体(LFA1)的结合诱导了转录信号(AP-1)，从而导致C3的转录。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“适合性”中的关键作用。相应地，表现为白细胞粘附病1(LAD-1)的LFA-1缺陷患者的T细胞存在固有的炎症功能缺陷，可以通过恢复细胞内C3的表达来按比例恢复。这项研究发表在2020年的《免疫》杂志上。 由于SARS冠状病毒(SARS-CoV2)的大流行，我们的主要努力受到了限制，我们不得不转移重点，为我们对SARS-CoV2的了解做出贡献。我们目前有两份手稿正在审查中，有望在21财年出版。这两篇手稿的重点都是通过主要由局部产生的因子来调节肺组织的局部炎症。

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.