Immunomodulatory function of inflammasomes in human primary dendritic cells

树突状细胞(DC)在协调免疫反应中起着关键作用。树突状细胞在细胞膜上配备了各种受体，可以感知组织微环境中的危险信号和病原体。炎症体在针对某些病原体的免疫反应中发挥着关键作用，但也在炎症性疾病和癌症的发病机制中发挥着关键作用。这种多蛋白信号复合体的形成需要TLR介导的初始启动步骤和导致生物活性细胞因子分泌的第二激活步骤。通常，炎性小体的激活会导致上睑下垂，这是一种通过激活caspase-1介导的炎性细胞死亡。以前，我们可以证明人类cDC2可以进入高度激活状态，其特征是在没有下垂的情况下炎性小体激活。对于人类cDC2，最近描述了两个亚群，即DC2和DC3，其功能专门化迄今尚不清楚。我们的初步数据表明，DC2和DC3对高激活的炎症体配体的反应不同。此外，我们还提示，在人类乳腺癌活检组织中，DC2和DC3的比率与某些乳腺癌亚型有关，表明在肿瘤控制中具有亚组特异性功能。此外，炎症体配体oxPAPC，一种氧化磷脂的混合物，在人CDC2中诱导了相当强的免疫抑制表型。这种氧化的磷脂已经在肿瘤中被发现，强调了在cDC2亚群的免疫抑制中的潜在作用。我们在这里假设DC2和DC3在免疫反应的极化中发挥不同的作用，依赖于炎症体刺激。了解炎症小体介导的免疫调节对于推进肿瘤和自身免疫性疾病的治疗具有重要意义。在这里提出的项目中，我们将集中在两个人类初级cDC2亚群的功能特征上。我们将进一步研究在人类DC亚群中过度激活与耐受/免疫抑制的调节。

Dendritic cells (DCs) play a pivotal role in orchestrating immune responses. Equipped with various receptors in the membrane, DCs sense the tissue microenvironment for danger signals and pathogens. Inflammasomes play a pivotal role in the immune response against certain pathogens, but also in the pathogenesis of inflammatory disorders and cancer. The formation of this multiprotein signaling complex requires a TLR-mediated initial priming step and a second activation step leading to the secretion of the bioactive cytokines. Usually, the activation of the inflammasome induces pyroptosis, an inflammatory cell death mediated by the activation of caspase-1. Previously, we could show that human cDC2 can enter a state of hyperactivation, which is characterized by inflammasome activation in the absence of pyroptosis. For human cDC2, two subpopulations, namely DC2 and DC3, with so far unclear functional specialization have been recently described. Our preliminary data suggest that DC2 and DC3 differ in their response to hyperactivating inflammasome ligands. Moreover, we have hints that in human breast cancer biopsies the ratio of DC2 to DC3 is associated with certain breast cancer subtypes, indicating a subset specific function in tumor control. Further, the inflammasome ligand oxPAPC, a mixture of oxidized phospholipids, induced a rather immunosuppressive phenotype in human cDC2. Such oxidized phospholipids have been identified in tumors underlining a potential role in the immunosuppression of cDC2 subsets. We here hypothesize that DC2 and DC3 exert different roles in the polarization of immune responses in dependency on the inflammasome stimulus. Understanding the inflammasome-mediated immunomodulation is important for advancing therapies for tumors and autoimmune diseases. In the here proposed project, we will focus on the functional characterization of the two human primary cDC2 subpopulations. We further will study the regulation of hyperactivation versus tolerance/immunosuppression in the human DC subpopulations.