Laboratory of Immune Regulation, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Int Immunol. 2020 May 8;32(5):307-319. doi: 10.1093/intimm/dxz082.
Interleukin-15 (IL-15) is a cytokine critical for maintenance of intestinal intra-epithelial lymphocytes (IELs), especially CD8αα + IELs (CD8αα 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 CD8αα IELs and NK IELs were significantly reduced in Vil-Cre IL-15cKO mice. By contrast, CD8αα IELs were unchanged in Tie2-Cre IL-15cKO mice, indicating that IL-15 produced by BECs and hematopoietic cells is dispensable for CD8αα IELs. Expression of an anti-apoptotic factor, Bcl-2, was decreased, whereas Fas expression was increased in CD8αα IELs of Vil-Cre IL-15cKO mice. Forced expression of Bcl-2 by a Bcl-2 transgene partially restored CD8αα IELs in Vil-Cre IL-15cKO mice, suggesting that some IL-15 signal other than Bcl-2 is required for maintenance of CD8αα IELs. Furthermore, granzyme B production was reduced, whereas PD-1 expression was increased in CD8αα 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.
白细胞介素 15（IL-15）是维持肠道上皮内淋巴细胞（IEL），特别是 CD8αα+IEL（CD8αα IEL）所必需的细胞因子。在肠道中，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，肠道中 IL-15 对 IEL 的确切作用仍不清楚。为了解决这个问题，我们生成了两种 IL-15 条件性敲除（IL-15cKO）小鼠：绒毛膜促性腺激素（Vil-Cre）和 Tie2-Cre IL-15cKO 小鼠。在 Vil-Cre IL-15cKO 小鼠中，IEC 来源的 IL-15 被特异性缺失，而在 Tie2-Cre IL-15cKO 小鼠中，BEC 和造血细胞产生的 IL-15 被缺失。在 Vil-Cre IL-15cKO 小鼠中，CD8αα IEL 和 NK IEL 的细胞数量和频率显著减少。相比之下，在 Tie2-Cre IL-15cKO 小鼠中，CD8αα IEL 没有变化，表明 BEC 和造血细胞产生的 IL-15 对 CD8αα IEL 是可有可无的。在 Vil-Cre IL-15cKO 小鼠的 CD8αα IEL 中，抗凋亡因子 Bcl-2 的表达减少，而 Fas 的表达增加。通过 Bcl-2 转基因的强制表达，部分恢复了 Vil-Cre IL-15cKO 小鼠中的 CD8αα IEL，表明维持 CD8αα IEL 需要除 Bcl-2 以外的一些 IL-15 信号。此外，在 Vil-Cre IL-15cKO 小鼠的 CD8αα IEL 中，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 通过促进其存活和功能成熟对 IEL 的稳态至关重要。
