Transcriptional profiling, cytokine requirement and function of myeloid-derived suppressor cells (MDSC) in the Mesocestoides corti Type 2 infection model

2 型中绦虫感染模型中骨髓源性抑制细胞 (MDSC) 的转录谱、细胞因子需求和功能

• 批准号: 527029760
• 负责人: Professor Dr. Manfred Lutz
• 金额: --
• 依托单位: Institut für Virologie und Immunbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/527029760?language=en
• 关键词: Transcriptional; profiling; cytokine; requirement; function

Myeloid-derived suppressor cells (MDSC) play important roles in the control of type 1 immune responses against tumors, viruses or bacteria. Factors leading to the generation of MDSC in these diseases are increasingly well understood. In contrast, reports on the occurrence and suppression mechanisms of MDSC in worm or parasite infections (type 2 immunity) are much less studied. While crucial differences for the polarization of macrophages, dendritic cells and T helper cells between type 1 and 2 infections are well documented, it is unclear whether such a dichotomy also occurs for MDSC. Since factors like GM-CSF, IFN-g and iNOS, hallmarks of type 1 immunity, do not occur or only marginally occur in type 2 immunity, other cytokines and effectors must lead to the generation and activation of MDSC in type 2 immunity. Our preliminary data indicate that IL-3 and Arg1 both typical characteristics of type 2 immunity may represent such factors. Our preliminary data show the successful generation of MDSC by IL-3 in vitro and the enriched frequencies of Arg1 producing MDSC in the type 2 immunity cestode model of Mesocestoides corti infection. Here we aim to employ state-of the art mouse models, cytokine blocking antibodies or drugs, as well as single cells RNA-sequencing to characterize MDSC in this type 2 infection. We will employ the M. corti infection model to investigate 1) the functional role of granulocytic and monocytic MDSC subsets during different stages of infection for suppression of T cells and dendritic cells, 2) the role of IL-3 as compared with GM-CSF for MDSC generation and 3) Arg1 as a suppressor mechanism compared with iNOS. The results will allow not only reveal phenotypical, transcriptional and functional differences between MDSC subsets in type 1 versus type 2 infection, but we will also test whether interference with MDSC generation or function represents a therapeutic option in type 2 infections. Overall, MDSC in type 2 infections are insufficiently investigated and are the subject of our project proposal. Since these diseases often involve chronic diseases with severe burdens and also fatal consequences, a better understanding of MDSC induction in type 2 infections and the identification of new avenues for immune intervention is of considerable clinical importance.

髓系来源的抑制细胞(MDSC)在控制针对肿瘤、病毒或细菌的1型免疫反应中发挥着重要作用。在这些疾病中，导致MDSC产生的因素越来越被人们所了解。相比之下，有关MDSC在蠕虫或寄生虫感染(2型免疫)中的发生和抑制机制的报道要少得多。虽然1型和2型感染之间巨噬细胞、树突状细胞和辅助性T细胞极化的关键差异已有文献记载，但尚不清楚这种二分法是否也发生在MDSC中。由于1型免疫的标志物GM-CSF、干扰素-g和iNOS等因子在2型免疫中不存在或仅有少量出现，因此在2型免疫中其他细胞因子和效应物必须导致MDSC的产生和激活。我们的初步数据表明，IL-3和Arg1都是2型免疫的典型特征，可能代表了这些因素。我们的初步数据表明，IL-3在体外成功地生成了MDSC，并在Corti感染的2型免疫寄生虫模型中发现了产生MDSC的Arg1的富集率。在这里，我们的目标是使用最先进的小鼠模型、细胞因子阻断抗体或药物，以及单细胞RNA测序来表征这种2型感染中的MDSC。我们将使用M.Corti感染模型来研究1)粒细胞和单核细胞MDSC亚群在感染的不同阶段对T细胞和树突状细胞的抑制作用，2)IL-3与GM-CSF在MDSC产生中的作用，以及3)Arg1与iNOS作为抑制机制的比较。这些结果不仅可以揭示1型和2型感染的MDSC亚群在表型、转录和功能上的差异，而且我们还将测试干扰MDSC的生成或功能是否代表了2型感染的治疗选择。总体而言，2型感染中的MDSC调查不足，是我们项目提案的主题。由于这些疾病往往涉及具有严重负担和致命后果的慢性疾病，因此更好地了解2型感染中MDSC的诱导和确定免疫干预的新途径具有相当重要的临床意义。