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研究生： 黃慧瑜
Huang, Hui-Yu
論文名稱： 介白素-33影響新生兒肺部介白素-4誘發的第二群自然類淋巴球細胞亞群發育
IL-33 affects the IL-4-induced development of group 2 innate lymphoid cell subpopulations in neonatal lungs
指導教授： 謝奇璋
Shieh, Chi-Chang
學位類別： 碩士
Master
系所名稱： 醫學院 - 臨床醫學研究所
Institute of Clinical Medicine
論文出版年： 2023
畢業學年度： 111
語文別： 英文
論文頁數： 42
中文關鍵詞： 新生兒 、肺泡化階段 、介白素-33 、介白素-4 、介白素-10 、介白素-10分泌型第二群自然類淋巴球 、過敏疾病
外文關鍵詞： neonate, alveolarization phase, IL-33, IL-4, IL-10, IL-10-producing ILC2, allergic disease
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    • 新生兒時期肺泡化階段中大量的介白素-33是由第二型肺泡細胞所分泌。介白素-33可促進肺部第二型免疫反應和第二群自然類淋巴球發育。過去研究中發現介白素-4可以誘導一群能分泌介白素-10的第二群自然類淋巴球於小鼠肺部環境中。然而，介白素-10分泌型第二群自然免疫類淋巴球細胞是否能被誘導以及受介白素-33的調控於新生兒肺部仍然未知。因此，我們想要探討介白素-33在新生兒肺部自然類淋巴球族群發展中的調控角色。我們使用流式細胞儀去區分自然類淋巴球細胞族群、骨髓細胞族群，以及檢測第二群自然類淋巴球細胞相關功能的細胞激素於野生型和介白素-33缺乏的小鼠肺部中。我們發現第二型免疫細胞的數量顯著降低於出生後7至28天的介白素-33缺乏的小鼠相較於野生型小鼠。然而，第二群自然類淋巴球佔自然類淋巴球的比例在介白素-33缺乏和野生型小鼠肺部中則相差不多。新生時期肺部介白素-4和介白素-10的量在介白素-33缺乏的小鼠中相較野生型小鼠來得低。流式細胞儀分析新生野生型小鼠的肺部有較多的介白素-10分泌型第二群自然類淋巴球數量相較於介白素-33缺乏的小鼠。肺部分選出的新生鼠第二型自然類淋巴球，而非成鼠第二型自然類淋巴球，在IL-33存在下可受到介白素-4和視黃酸的刺激後轉群成介白素-10分泌型第二群自然類淋巴球。我們的結果強調新生兒肺部肺泡化階段中介白素-33扮演促進分泌介白素-10的第二群自然類淋巴球分化的角色。過去研究已發現肺部介白素-10分泌型第二群自然類淋巴球在過敏性疾病中扮演免疫抑制的角色，因此受介白素-33刺激的介白素-10分泌型第二群自然類淋巴球在新生兒時期的肺部發育可能對於未來維持肺部免疫穩定狀態有其重要性。

    Abundant Interleukin-33 (IL-33) is produced by alveolar type 2 cells during lung alveolarization phase in the neonatal stage. It triggers lung type 2 immune response and facilitate group 2 innate lymphoid cell (ILC2) development. IL-4 has been found to induce regulatory IL-10-producing ILC2s in the lung environment of mice. However, it is still unknown whether IL-10-producing ILC2s are induced in neonatal lungs and regulated by IL-33. Therefore, we aimed to investigate the regulatory role of IL-33 in the development of lung innate lymphoid cell (ILC) populations during neonatal period. We used flow cytometry to characterize ILC populations, myeloid cell populations and measured the cytokines relevant to ILC2 functions in the lungs of WT and IL-33-/- mice. We found that the numbers of type 2 immune cells significantly decreased in the lungs of IL-33-/- mice from around PND7 to PND28 when compared with WT mice. However, the proportion of ILC2s in the total ILCs was comparable in lung between WT and IL-33-/- mice. The whole lung cytokine levels of IL-4 and IL-10 were lower in IL-33-/- mice when compared with WT mice during the neonatal period. The numbers of IL-10-producing ILC2 cells were found more in the neonatal lungs of WT mice than in IL-33-/- mice, as determined by flow cytometry analysis. Lung sorted neonatal ILC2s, but not adult ILC2s, could be induced by IL-4 and retinoid acid (RA) to differentiate to ILC2-10 in the presence of IL-33. Our results highlight the role of IL-33 in promoting the differentiation of ILC2s towards IL-10-producing ILC2s in lung during the neonatal alveolarization phase. Since ILC2-10 cells have been found to play an immune suppressive role in allergic diseases, the development of ILC2-10 cells induced by IL-33 in lung during the neonatal period may be important to maintain lung homeostasis throughout life.

    Abstract I 中文摘要 III 誌謝 IV Abbreviations V Chapter 1. Introduction 1 1.1 Neonatal lung development 1 1.2 Immune cells development in neonatal lung 1 1.3 Upregulation of type 2 immunity during lung alveolarization phase 2 1.4 Plasticity of group 2 innate lymphoid cell in type 2 immunity 3 1.5 The factors inducing IL-10-producing ILC2s 4 1.6 IL-10-producing ILC2s in asthma 6 Chapter 2. Materials and Methods 7 2.1 Experimental animals 7 2.2 Flow cytometry analysis 7 2.2.1 Preparation of single cell suspensions from lung tissue 7 2.2.2 ILC populations and myeloid cells detection by flow cytometry 7 2.3 Lung cytokine quantification 9 2.4 ILC2 in vitro culture 9 2.5 Statistical analysis 10 Chapter 3. Results 11 3.1 Although the development of pulmonary type 2 immune cells (ILC2s) was lower in number in neonatal IL-33-deficient mice, the proportion of ILC2s in total ILCs appeared relatively normal. 11 3.2 IL-33-deficient mice had lower levels of IL-4, IL-10 and IL-13 but comparable levels of IFN-γ and IL-17A in the lung during the neonatal period. 13 3.3 IL-33-deficient neonatal mice had lower numbers of IL-10-producing ILC2 but equal numbers of IL-13-producing ILC2 in the lung when compared with wild type newborn mice. 14 3.4 Neonatal, but not adult, pulmonary ILC2 can be induced by IL-4 and retinoid acid to differentiate to ILC2-10 in the presence of IL-33. 15 Chapter 4. Discussion 17 4.1 ILC development in lung during neonatal period 17 4.2 The pleiotropic effects of IL-33 on group 2 innate lymphoid cells 19 4.3 ILC2-10 correlating to clinical allergic responses 21 Chapter 5. Figures and Tables 23 Figure 1. 23 Although the development of pulmonary type 2 immune cells (ILC2s) was lower in number in neonatal IL-33-deficient mice, the proportion of ILC2s in total ILCs appeared relatively normal. 28 Figure 2. 29 IL-33-deficient mice had lower levels of IL-4, IL-10 and IL-13 but comparable levels of IFN-γ and IL-17A in the lung during the neonatal period. 30 Figure 3. 31 IL-33-deficient neonatal mice had lower numbers of IL-10-producing ILC2 but equal numbers of IL-13-producing ILC2 in the lung when compared with wild type newborn mice. 33 Figure 4. 34 Neonatal, but not adult, pulmonary ILC2 can be induced by IL-4 and retinoid acid to differentiate to ILC2-10 in the presence of IL-33. 36 Table 1. Antibodies for the characterization of ILC/myeloid cell populations and ILC2 sorting 37 Chapter 6. References 40

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