Exploring the thymic origin of group 2 innate lymphoid cells

探索第 2 组先天淋巴细胞的胸腺起源

• 批准号: 9295975
• 负责人: Xiao-Hong Sun
• 金额: $ 54.43万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295975
• 关键词: Address; Age; Allergic; Animal Model; Asthma; Autoimmune Diseases; B-Lymphocytes; Biological; Bone Marrow; CD28 gene; Cell Differentiation process; Cells; Child; Childhood Asthma; Collection; Common Lymphoid Progenitor; DNA Binding; Data; Dependence; Development; Disease; Down-Regulation; E protein; Environment; Family Study; GATA3 gene; Gene Expression; Gene Targeting; Genes; Growth; Helix-Turn-Helix Motifs; Heterodimerization; Homeostasis; Homologous Gene; Immune System Diseases; Immune response; Immune system; In Vitro; Infection; Innate Immune Response; Interleukin-2; Interleukin-7; Knowledge; Laboratories; Link; Location; Lung; Lymphoid; Lymphoid Cell; Mesentery; Molecular Profiling; Multipotent Stem Cells; Mus; Organ; Output; Pathology; Play; Production; Protein Inhibition; Proteins; Reagent; Respiratory System; Role; Secure; Signal Pathway; Signal Transduction; Site; Skin; Stem cells; T-Lymphocyte; Testing; Thymus Gland; Transgenes; Transgenic Mice; Transgenic Organisms; Wild Type Mouse; allergic response; bone cell; cell type; clinically significant; design; experimental study; fighting; follow-up; helix-loop-helix protein differentiation inhibitor; inducible gene expression; inhibitor/antagonist; insight; interest; lymph nodes; multipotent cell; notch protein; novel therapeutic intervention; pathogen; prevent; progenitor; protein E; thymocyte; transcription factor; transcriptome sequencing

Project Summary Innate lymphoid cells (ILC) are new important players in mounting innate immune responses to various pathogens as well as in the development of diverse immunological diseases. For example, increased levels of group 2 ILCs (ILC2s) has been linked to asthma and allergic illnesses in the respiratory system and skin. How ILCs are formed is just beginning to be understood. Current dogma states that ILCs are derived from common lymphoid progenitors (CLP) in the bone marrow. Several subsets of ILC progenitors that give rise to all ILC types without producing B or T lymphoid cells have been identified and thought to lie downstream of CLP. However, it is not known if ILCs can also originate from other multipotent progenitors and at different locations besides the bone marrow. We have obtained compelling evidence which allows us to propose that the thymus is capable of producing ILC2s, and preferentially supply them to the lung. In this proposal, we will devote Aim1 to further characterizing this phenomenon. We will first determine if ILC2 counts in the lung decrease as thymic output declines with age. We will then compare lung ILC2 levels in mice with or without thymus (nu/+ vs. nu/nu). We will next obtain gene expression profiles of ILC2 cells in the bone marrow and thymus, as well as lung ILC2s derived from the bone marrow and thymus. Finally, we will identify the progenitors in the thymus that are capable of generating ILC2s. We have also garnered strong evidence that down-regulating E protein activities promotes ILC2 differentiation in the thymus. This is consistent with the essential role of Id2, the inhibitor of E proteins in ILC differentiation. Since the underlying mechanisms by which Id2 controls ILC differentiation is unknown, we will designate Aim2 for probing the impact of altered E protein activities on ILC2 differentiation from multipotent progenitors of the bone marrow and thymus, as well as on the proliferation and survival of ILC2s. We are also interested in testing the idea that Id2 down-regulates E proteins to enhance IL-2/IL-7 and CD28 signaling, which are important for ILC2 proliferation and survival. We will determine if E protein inhibition could alleviate the need for IL-2 in ILC2 differentiation in vitro and rescue ILC2 development in IL-7-/-, IL-2Rγc-/- and Icos-/- mice. Finally, we will augment E protein activities in ILC2 cells to search for target genes that are responsible for suppressing the innate lymphoid fate and promoting the adaptive lymphoid fate. In summary, we believe our studies will lead to paradigm-shifting discoveries that will enrich our knowledge about the ontogeny of ILC2 cells and provide insight into diseases such as childhood asthma, in which thymus-derived ILC2s likely play a causative role.

项目概要 先天淋巴样细胞 (ILC) 是对各种疾病产生先天免疫反应的新的重要参与者。 病原体以及多种免疫疾病的发展。例如，增加水平 第 2 组 ILC (ILC2) 与哮喘以及呼吸系统和皮肤过敏性疾病有关。如何 ILC 的形成才刚刚开始被人们所理解。当前的教条指出，ILC 源自共同的 骨髓中的淋巴祖细胞（CLP）。产生所有 ILC 的 ILC 祖细胞的几个子集 不产生 B 或 T 淋巴细胞的类型已被鉴定，并被认为位于 CLP 的下游。 然而，尚不清楚 ILC 是否也可以起源于其他多能祖细胞并且位于不同的位置 除了骨髓之外。我们已经获得了令人信服的证据，使我们能够提出胸腺 能够产生ILC2，并优先将其供应至肺部。在这个提案中，我们将致力于 Aim1 进一步表征这一现象。我们首先确定肺中的 ILC2 计数是否减少： 胸腺输出随着年龄的增长而下降。然后，我们将比较有或没有胸腺的小鼠的肺 ILC2 水平 (nu/+ 对比 nu/nu)。接下来我们还将获得骨髓和胸腺中 ILC2 细胞的基因表达谱 肺 ILC2 源自骨髓和胸腺。最后，我们将鉴定胸腺中的祖细胞 能够产生ILC2。 我们还获得了强有力的证据表明下调 E 蛋白活性可促进 ILC2 胸腺中的分化。这与 ILC 中 E 蛋白抑制剂 Id2 的重要作用一致 差异化。由于 Id2 控制 ILC 分化的潜在机制尚不清楚，我们将 指定 Aim2 用于探究 E 蛋白活性改变对 ILC2 从多能分化的影响 骨髓和胸腺祖细胞，以及 ILC2 的增殖和存活。我们也是 有兴趣测试 Id2 下调 E 蛋白以增强 IL-2/IL-7 和 CD28 信号传导的想法， 这对于 ILC2 增殖和存活很重要。我们将确定 E 蛋白抑制是否可以缓解 体外 ILC2 分化需要 IL-2，并拯救 IL-7-/-、IL-2Rγc-/- 和 Icos-/- 中的 ILC2 发育 老鼠。最后，我们将增强 ILC2 细胞中 E 蛋白的活性，以寻找负责的靶基因 用于抑制先天性淋巴命运并促进适应性淋巴命运。 总之，我们相信我们的研究将带来范式转变的发现，从而丰富我们的研究 有关 ILC2 细胞个体发育的知识，并提供对儿童哮喘等疾病的深入了解 胸腺来源的 ILC2 可能发挥了致病作用。