Intestinal epithelial cell-derived IL-15 determines local maintenance and maturation of intra-epithelial lymphocytes in the intestine
Intestinal epithelial cell-derived IL-15 determines local maintenance and maturation of intra-epithelial lymphocytes in the intestine
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DOI：
10.1093/intimm/dxz082
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发表时间：
2020-05-01
影响因子：
4.4
通讯作者：
Ikuta, Koichi
中科院分区：
文献类型：
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作者：
Zhu, Yuanbo;Cui, Guangwei;Ikuta, Koichi
白介素15(IL-15)是维持肠道上皮内淋巴细胞(IEL)，特别是CD8α(+)IEL(CD8αIEL)的关键细胞因子。在肠道，IL-15由肠上皮细胞(IECS)、血管内皮细胞(BECs)和造血细胞产生。然而，肠道IL-15在IELs中的确切作用仍不清楚。为了解决这个问题，我们产生了两种IL-15条件基因敲除(IL-15cKO)小鼠：Villin-Cre(VIL-Cre)和Tie2-Cre IL-15cKO小鼠。IL-15cKO小鼠特异性缺失IEC来源的IL-15，而Tie2-Cre IL-15cKO小鼠缺失BEC和造血细胞产生的IL-15。IL-15cKO小鼠CD8αIELs和NK IELs的细胞数量和频率均显著降低。而Tie2-Cre IL-15cKO小鼠CD8αIELs无明显变化，提示BECs和造血细胞产生的IL-15对CD8αIELs是必需的。IL-15cKO小鼠CD8αIELs中抗凋亡因子Bcl2的表达降低，而Fas的表达增加。在VIL-CRE IL-15cKO小鼠中，通过转Bcl2基因强迫表达Bcl2可部分恢复CD8αIELs，提示CD8αIELs的维持需要一些非Bcl2的IL-15信号。此外，VIL-Cre IL-15cKO小鼠CD8αIELs颗粒酶B的产生减少，而PD-1的表达增加。这些结果共同表明，IEC来源的IL-15通过促进IELs的存活和功能成熟，对IELs的动态平衡是必不可少的。
Interleukin-15 (IL-15) is a cytokine critical for maintenance of intestinal intra-epithelial lymphocytes (IELs), especially CD8 alpha alpha(+) IELs (CD8 alpha alpha IELs). In the intestine, IL-15 is produced by intestinal epithelial cells (IECs), blood vascular endothelial cells (BECs) and hematopoietic cells. However, the precise role of intestinal IL-15 on IELs is still unknown. To address the question, we generated two kinds of IL-15 conditional knockout (IL-15cKO) mice: villin-Cre (Vil-Cre) and Tie2-Cre IL-15cKO mice. IEC-derived IL-15 was specifically deleted in Vil-Cre IL-15cKO mice, whereas IL-15 produced by BECs and hematopoietic cells was deleted in Tie2-Cre IL-15cKO mice. The cell number and frequency of CD8 alpha alpha IELs and NK IELs were significantly reduced in Vil-Cre IL-15cKO mice. By contrast, CD8 alpha alpha IELs were unchanged in Tie2-Cre IL-15cKO mice, indicating that IL-15 produced by BECs and hematopoietic cells is dispensable for CD8 alpha alpha IELs. Expression of an anti-apoptotic factor, Bcl-2, was decreased, whereas Fas expression was increased in CD8 alpha alpha IELs of Vil-Cre IL-15cKO mice. Forced expression of Bcl-2 by a Bcl-2 transgene partially restored CD8 alpha alpha IELs in Vil-Cre IL-15cKO mice, suggesting that some IL-15 signal other than Bcl-2 is required for maintenance of CD8 alpha alpha IELs. Furthermore, granzyme B production was reduced, whereas PD-1 expression was increased in CD8 alpha alpha IELs of Vil-Cre IL-15cKO mice. These results collectively suggested that IEC-derived IL-15 is essential for homeostasis of IELs by promoting their survival and functional maturation.