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

骨髓源性抑制细胞（MDSC）在控制针对肿瘤、病毒或细菌的1型免疫应答中起重要作用。在这些疾病中导致MDSC产生的因素越来越清楚。相比之下，关于蠕虫或寄生虫感染（2型免疫）中MDSC的发生和抑制机制的报告研究得更少。虽然1型和2型感染之间巨噬细胞，树突状细胞和T辅助细胞极化的关键差异已得到充分证明，但尚不清楚MDSC是否也发生这种二分法。由于因子如GM-CSF、IFN-g和iNOS（1型免疫的标志）在2型免疫中不发生或仅少量发生，因此其他细胞因子和效应物必须导致2型免疫中MDSC的产生和活化。我们的初步数据表明，IL-3和Arg 1这两个典型的2型免疫特征可能代表了这些因素。我们的初步数据显示，成功地在体外产生MDSC的IL-3和Arg 1产生MDSC的富集频率在2型免疫绦虫模型的Mesocestoides Corti感染。在这里，我们的目标是采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，以表征MDSC在这种2型感染。我们将使用M。Corti感染模型，以研究1）粒细胞和单核细胞MDSC亚群在感染的不同阶段对抑制T细胞和树突细胞的功能作用，2）与GM-CSF相比IL-3对MDSC产生的作用和3）与iNOS相比Arg 1作为抑制机制。这些结果不仅可以揭示1型与2型感染中MDSC亚群之间的表型，转录和功能差异，而且我们还将测试干扰MDSC生成或功能是否代表2型感染的治疗选择。总的来说，MDSC在2型感染中的研究还不够充分，这是我们项目提案的主题。由于这些疾病往往涉及慢性疾病，严重的负担，也致命的后果，更好地了解MDSC诱导2型感染和免疫干预的新途径的识别是相当重要的临床意义。

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.