Lnk prevents inflammatory CD8+T-cell proliferation and contributes to intestinal homeostasis
Lnk prevents inflammatory CD8+T-cell proliferation and contributes to intestinal homeostasis
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DOI：
10.1002/eji.201343883
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发表时间：
2014-06-01
影响因子：
5.4
通讯作者：
Takaki, Satoshi
中科院分区：
文献类型：
--
作者：
Katayama, Hiroko;Mori, Taizo;Takaki, Satoshi
细胞内接头 Lnk（也称为 SH2B3）调节控制淋巴造血的细胞因子信号，Lnk-/- 小鼠具有扩增的 B 细胞、巨核细胞和造血干细胞群。此外，在骨髓增生性疾病患者中发现了 LNK 基因突变，而 LNK 多态性最近与炎症和自身免疫性疾病（包括乳糜泻）相关。在这里，我们描述了 Lnk 在控制炎症 CD8+ T 细胞增殖和肠道稳态中以前未被认识的功能。来自新生成的 Lnk-Venus 报告小鼠的成熟 T 细胞具有较低但大量的 Lnk 表达，而在淋巴细胞减少条件下的稳态 T 细胞增殖过程中，Lnk 表达下调。研究发现 Lnk-/- 小鼠中 CD44hiIFN-+CD8+ 效应细胞或记忆 T 细胞的数量增加，并且小肠绒毛也出现缩短。 Lnk-/- CD8+ T 细胞在 IL-15 刺激下存活时间更长，甚至在非淋巴细胞减少的宿主中也能增殖。将 Lnk-/- CD8+ T 细胞与 WT CD4+ T 细胞一起转移到 Rag2 缺陷小鼠体内，重现了绒毛异常的迹象。我们的结果揭示了 Lnk 与免疫细胞介导的肠道组织破坏之间的联系。
The intracellular adaptor Lnk (also known as SH2B3) regulates cytokine signals that control lymphohematopoiesis, and Lnk-/- mice have expanded B-cell, megakaryocyte, and hematopoietic stem-cell populations. Moreover, mutations in the LNK gene are found in patients with myeloproliferative disease, whereas LNK polymorphisms have recently been associated with inflammatory and autoimmune diseases, including celiac disease. Here, we describe a previously unrecognized function of Lnk in the control of inflammatory CD8+ T-cell proliferation and in intestinal homeostasis. Mature Tcells from newly generated Lnk-Venus reporter mice had low but substantial expression of Lnk, whereas Lnk expression was downregulated during homeostatic T-cell proliferation under lymphopenic conditions. The numbers of CD44hiIFN-+CD8+ effector or memory Tcells were found to be increased in Lnk-/- mice, which also exhibited shortening of villi in the small intestine. Lnk-/- CD8+ Tcells survived longer in response to stimulation with IL-15 and proliferated even in nonlymphopenic hosts. Transfer of Lnk-/- CD8+ Tcells together with WT CD4+ Tcells into Rag2-deficient mice recapitulated a sign of villous abnormality. Our results reveal a link between Lnk and immune cell-mediated intestinal tissue destruction.