The role of the intracellular complement system - the complosome - in Th1 biology

A.我们在理解C3基因表达如何在T细胞和其他免疫细胞中调节方面取得了重大进展。我们发现由整合素LFA-1介导的信号（在免疫细胞渗出到组织中期间参与）是C3的主要诱导物。因此，LFA-1缺乏的患者不能上调免疫细胞中的C3，因此缺乏正常的Th 1、CTL和IL-1b产生巨噬细胞（Kolev和West，Immunity，2020）。 B。我们现在也已经能够理清确切的分子机制，其中CD 46的胞内结构域诱导Th 1相关的基因和活动的人CD 4 + T细胞。这是通过与细胞核中的特定转录因子直接相互作用而发生的（手稿正在准备中）。 C.我们在理解补体如何在Th 1细胞中共同诱导IL-10并启动其关闭程序方面取得了同样的进展。这些新的功能涉及控制表达诱导的代谢酶调节脂质和氨基酸的使用（手稿提交和准备）。 D.为了尝试以前所未有的深度理解幼稚和记忆性CD 4+和CD 8 + T细胞活化的信号传导事件，我们已经进行了人类分选T细胞随时间的第一次比较scRNA-seq分析，并与U-Penn的Zhang实验室合作，利用整合多个未知多变量概率分布的新算法分析数据（Bibby et al.，Cell Reports，2022）。 E.我们现在还表明，CD 46控制谷氨酰胺和精氨酸流入T细胞，并通过随后控制谷胱甘肽酶1活性来控制Th 1关闭程序（West等人，豁免权，2023年）

A. We have made major progress in understanding how C3 gene expression is regulated in T and other immune cells. We found that signals mediated by the integrin LFA-1 (engaged during diapedesis of immune cells into tissues) is a master inducer of C3. In consequence, patients with deficiency in LFA-1 cannot upregulate C3 in immune cells and, thus, lack normal Th1, CTL and IL-1b producing macrophages (Kolev and West, Immunity, 2020). B. We have now also been able to detangle the exact molecular mechanisms by which the intracellular domain of CD46 induces Th1-related genes and activities in human CD4+ T cells. This occurs via direct interaction with specific transcription factors in the nucleus (manuscript in preparation). C. We have made equal progress in understanding how the complosome co-induces IL-10 in Th1 cells and initiates their shutdown program. These novel functions of the complosome involve the controlled expression induction of metabolic enzymes regulating lipid and amino acid usage (manuscript submitted and in preparation). D. In an attempt to understand the signaling event underlying naive and memory CD4+ and CD8+ T cell activation in unprecedented depth, we have performed the first comparative scRNA-seq analysis of human sorted T cells over time and analyzed the data utilizing a novel algorithm integrating multiple unknown multivariate probability distributions in collaboration with the Zhang laboratory at U-Penn (Bibby et al., Cell Reports, 2022). E. We have now also shown that CD46 controls glutamine and arginine influx into T cells and via subsequent control of arginase 1 activity the Th1 shutdown program (West et al., Immunity, 2023)