Myeloid derived IL-33 controls Treg responses during parasite infection

项目摘要 白细胞介素1（IL-1）细胞因子超家族成员IL-33驱动宿主对胃肠道（GI） 病原体通过机制尚不清楚。奇怪的是，IL-33反应性在不同的 淋巴细胞亚群决定了其促炎与抗炎作用，这表现在其促进 第2组先天性淋巴样细胞（ILC 2）或Foxp 3+调节性T细胞（TCF 3）。IL-33的来源 影响其生物学作用的因素在很大程度上被忽视，因为目前的范式是IL-33仅从 受损的结构细胞（例如上皮细胞谱系）。然而，我们最近公布的数据显示， 上皮细胞（IEC）衍生的IL-33驱动ILC 2应答和GI蠕虫免疫，而树突状细胞（DC）- 衍生的IL-33驱动ST 2 + Foxp 3 + Treg应答和蠕虫易感性。这一建议旨在了解 负责髓系中IL-33表达和产生的机制，并进一步研究 IL-33细胞环境是否控制炎症与免疫抑制之间的平衡， 原生动物感染和蠕虫感染一样。我们的项目测试了核心假设， IL-33的来源决定了IL-33在GI寄生虫期间起保护作用还是致病作用 通过控制肠道Treg亚群扩增来控制感染。我们将在两个具体的实验中验证这一假设。 目标（SA）。SA 1中提出的实验将：a）对IL-33+与IL-33- DC进行转录谱分析，以确定是否 表达IL-33的APC构成了一个独特的亚群，B）采用显微镜和成像质谱法， 了解这些细胞所在的组织小生境，以及c）确定DC衍生的IL-33是否对 通过微生物依赖性机制维持和/或诱导不同的Foxp 3 + Treg亚群。 SA 2将产生允许在不同DC亚群和组织巨噬细胞群体中缺失IL-33的小鼠， 确定它们对肠道组织稳态和宿主对GI病原体的保护作用的影响。最后，我们将 确定上皮源性与髓源性IL-33是否控制微生物生态失调和病理结果 口腔弓形虫感染后。总的来说，这个项目旨在扩大基本的理解 细胞因子产生的细胞环境如何影响对重要的人类胃肠道病原体的免疫力。

Project Summary The interleukin 1 (IL-1) cytokine superfamily member IL-33 drives host protection against gastrointestinal (GI) pathogens through mechanisms that remain unclear. Paradoxically, IL-33 responsiveness in different lymphocyte subsets dictates its pro- vs. anti-inflammatory roles evinced by its ability to promote expansion of group 2 innate lymphoid cells (ILC2) or Foxp3+ regulatory T cells (Tregs), respectively. Whether source of IL-33 influences its biological role has been largely ignored due the current paradigm that IL-33 is only released from damaged structural cells (e.g. epithelial cell lineages). However, our recently published data show that intestinal epithelial cell (IEC)-derived IL-33 drives ILC2 responses and GI helminth immunity, whereas dendritic cell (DC)- derived IL-33 drives ST2+Foxp3+ Treg responses and helminth susceptibility. This proposal seeks to understand the mechanisms responsible for IL-33 expression and production in the myeloid lineage and further investigates whether IL-33 cellular context controls the balance between inflammation vs. immunosuppression during protozoan infections as it does in helminth infections. Our project tests the central hypothesis that cellular source of IL-33 determines whether IL-33 serves a protective or pathogenic role during GI parasite infection through controlling intestinal Treg subset expansion. We will test this hypothesis in two specific aims (SA). Experiments proposed in SA1 will: a) transcriptionally profile IL-33+ vs. IL-33- DC to determine whether IL-33 expressing APC constitute a distinct subset, b) employ microscopy and imaging mass spectrometry to understand the tissue niches where these cells reside, and c) determine whether DC-derived IL-33 is critical for the maintenance and/or induction of distinct subsets of Foxp3+ Treg through microbial-dependent mechanisms. SA2 will generate mice that allow IL-33 deletion in distinct DC-subsets and tissue macrophage populations to determine their impact on intestinal tissue homeostasis and host protection against GI pathogens. Lastly, we will determine whether epithelial vs. myeloid derived-IL-33 controls microbial dysbiosis and the pathological outcome following oral Toxoplasma gondii infection. Taken together, this project seeks to expand the basic understanding of how the cellular context of cytokine production impacts immunity against important human GI pathogens.