Exploring the thymic origin of group 2 innate lymphoid cells

项目摘要 先天性淋巴样细胞（ILC）是对各种免疫系统的先天性免疫应答的新的重要参与者。 病原体以及各种免疫性疾病的发展。例如， 组2 ILC（ILC 2）与呼吸系统和皮肤中的哮喘和过敏性疾病有关。如何 ILC的形成才刚刚开始被理解。目前的教条指出，国际劳工公约是从共同的 骨髓中的淋巴样祖细胞（CLP）。产生所有ILC的ILC祖细胞的几个子集 不产生B或T淋巴样细胞的类型已被鉴定并被认为位于CLP的下游。 然而，目前尚不清楚ILC是否也可以起源于其他多能祖细胞和不同的位置 除了骨髓我们已经获得了令人信服的证据，这使我们能够提出， 能够产生ILC 2，并优先将其供应给肺。在本提案中，我们将致力于Aim 1 进一步描述这种现象。我们将首先确定肺中的ILC 2计数是否减少， 胸腺输出随年龄增长而下降。然后，我们将比较有或没有胸腺的小鼠（nu/+）中的肺ILC 2水平 vs. nu/nu）。我们接下来还将获得骨髓和胸腺中ILC 2细胞的基因表达谱， 作为来自骨髓和胸腺的肺ILC 2。最后，我们将确定胸腺中的祖细胞 能够产生ILC 2的细胞。 我们还获得了强有力的证据表明，下调E蛋白活性促进ILC 2 胸腺的分化。这与ILC中E蛋白抑制剂Id 2的重要作用一致 分化由于Id 2控制ILC分化的潜在机制尚不清楚，我们将 命名为Aim 2，用于探测改变的E蛋白活性对ILC 2从多能细胞分化的影响。 骨髓和胸腺的祖细胞，以及ILC 2的增殖和存活。我们也 有兴趣测试Id 2下调E蛋白以增强IL-2/IL-7和CD 28信号传导的想法， 其对于ILC 2增殖和存活是重要的。我们将确定E蛋白抑制是否可以减轻 IL-7-/-、IL-2 R γc-/-和Icos-/-在ILC 2体外分化中对IL-2的需要和拯救ILC 2发育 小鼠最后，我们将增加ILC 2细胞中E蛋白的活性，以寻找与ILC 2细胞中E蛋白的表达相关的靶基因。 用于抑制先天性淋巴命运和促进适应性淋巴命运。 总之，我们相信我们的研究将导致范式转变的发现，这将丰富我们的 了解ILC 2细胞的个体发育，并提供对儿童哮喘等疾病的深入了解， 胸腺来源的ILC 2可能起致病作用。

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.