A Chimeric IL-7Rα/IL-2Rβ Receptor Promotes the Differentiation of T Cell Progenitors into B Cells and Type 2 Innate Lymphoid Cells.

IF 3.6 3区 医学 Q2 IMMUNOLOGY
Akihiro Shimba, Shizue Tani-Ichi, Kyoko Masuda, Guangwei Cui, Satoru Munakata, Shinya Abe, Satsuki Kitano, Hitoshi Miyachi, Hiroshi Kawamoto, Koichi Ikuta
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Abstract

IL-7 and IL-2 are evolutionarily related cytokines that play critical roles in the development and expansion of immune cells. Although both IL-7R and IL-2R activate similar signaling molecules, whether their signals have specific or overlapping functions during lymphocyte differentiation remains unclear. To address this question, we generated IL-7R α-chain (IL-7Rα)/IL-2R β-chain (IL-24β) (72R) knock-in mice expressing a chimeric receptor consisting of the extracellular domain of IL-7Rα and the intracellular domain of IL-2Rβ under the control of the endogenous IL-7Rα promoter. Notably, this 72R receptor induced higher levels of STAT5 and Akt phosphorylation in T cells. In the periphery of 72R mice, the number of T cells, B cells, and type 2 innate lymphoid cells (ILC2s) was increased, whereas early T cell progenitors and double-negative 2 thymocytes were reduced in the thymus. In addition, cell proliferation and Notch signaling were impaired in the early thymocytes of 72R mice, leading to their differentiation into thymic B cells. Interestingly, ILC2s were increased in the thymus of 72R mice. Early T cell progenitors from 72R mice, but not from wild-type mice, differentiated into NK cells and ILC2-like cells when cocultured with a thymic stromal cell line. Thus, this study indicates that the chimeric 72R receptor transduces more robust signals than the authentic IL-7Rα, thereby inducing the alternative differentiation of T cell progenitors into other cell lineages. This suggests that cytokine receptors may provide instructive signals for cell fate decisions.

嵌合型 IL-7Rα/IL-2Rβ 受体促进 T 细胞祖细胞分化为 B 细胞和 2 型先天性淋巴细胞
IL-7 和 IL-2 是进化相关的细胞因子,在免疫细胞的发育和扩增过程中发挥着关键作用。虽然IL-7R和IL-2R都能激活类似的信号分子,但它们的信号在淋巴细胞分化过程中是否具有特定或重叠的功能仍不清楚。为了解决这个问题,我们产生了IL-7R α-链(IL-7Rα)/IL-2R β-链(IL-24β)(72R)基因敲入小鼠,在内源性IL-7Rα启动子的控制下表达由IL-7Rα胞外结构域和IL-2Rβ胞内结构域组成的嵌合受体。值得注意的是,这种 72R 受体能诱导 T 细胞中更高水平的 STAT5 和 Akt 磷酸化。在 72R 小鼠的外周,T 细胞、B 细胞和 2 型先天性淋巴细胞(ILC2s)的数量增加,而胸腺中早期 T 细胞祖细胞和双阴性 2 型胸腺细胞的数量减少。此外,72R 小鼠早期胸腺细胞的细胞增殖和 Notch 信号转导受到影响,导致它们分化成胸腺 B 细胞。有趣的是,72R 小鼠胸腺中的 ILC2 增加了。72R 小鼠的早期 T 细胞祖细胞与胸腺基质细胞系共同培养后,可分化成 NK 细胞和 ILC2 样细胞,而野生型小鼠的 T 细胞祖细胞则不能分化成 NK 细胞和 ILC2 样细胞。因此,这项研究表明,嵌合 72R 受体比真正的 IL-7Rα 能传递更强的信号,从而诱导 T 细胞祖细胞分化成其他细胞系。这表明细胞因子受体可为细胞命运的决定提供指导性信号。
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来源期刊
Journal of immunology
Journal of immunology 医学-免疫学
CiteScore
8.20
自引率
2.30%
发文量
495
审稿时长
1 months
期刊介绍: The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)
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