Interleukin-15-Dependent T-Cell-like Innate Intraepithelial Lymphocytes Develop in the Intestine and Transform into Lymphomas in Celiac Disease
Interleukin-15-Dependent T-Cell-like Innate Intraepithelial Lymphocytes Develop in the Intestine and Transform into Lymphomas in Celiac Disease
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DOI：
10.1016/j.immuni.2016.07.018
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发表时间：
2016-09-20
期刊：
影响因子：
32.4
通讯作者：
Meresse, Bertrand
中科院分区：
文献类型：
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作者：
Ettersperger, Julien;Montcuquet, Nicolas;Meresse, Bertrand
缺乏抗原受体的肠上皮内淋巴细胞（IEL）的性质仍然存在争议。在此，我们发现，在人类和小鼠中，表达细胞内CD 3（iCD 3（+））的先天性肠道IEL响应TF NOTCH 1、白细胞介素-15（IL-15）和颗粒酶B信号，沿沿着Id 2转录因子（TF）非依赖性途径分化。在NOTCH 1激活的人造血前体中，IL-15诱导颗粒酶B，其将NOTCH 1切割成缺乏转录活性的肽。结果，T细胞分化所必需的NOTCH 1靶基因被沉默，前体被重编程为具有T细胞标记的先天细胞，包括细胞内CD 3和T细胞重排。在并发乳糜泻的上皮内淋巴瘤中，iCD 3（+）先天IEL获得Janus激酶1或信号转导和转录激活因子3的功能获得性突变，这增强了它们对IL-15的反应。总体而言，我们表征了肠道T细胞样先天IEL，破译了它们的分化途径，并显示了它们在乳糜泻中的恶性转化。
The nature of gut intraepithelial lymphocytes (IELs) lacking antigen receptors remains controversial. Herein we showed that, in humans and in mice, innate intestinal IELs expressing intracellular CD3 (iCD3(+)) differentiate along an Id2 transcription factor (TF)independent pathway in response to TF NOTCH1, interleukin-15 (IL-15), and Granzyme B signals. In NOTCH1-activated human hematopoietic precursors, IL-15 induced Granzyme B, which cleaved NOTCH1 into a peptide lacking transcriptional activity. As a result, NOTCH1 target genes indispensable for T cell differentiation were silenced and precursors were reprogrammed into innate cells with T cell marks including intracellular CD3 and T cell rearrangements. In the intraepithelial lymphoma complicating celiac disease, iCD3(+) innate IELs acquired gain-of-function mutations in Janus kinase 1 or Signal transducer and activator of transcription 3, which enhanced their response to IL-15. Overall we characterized gut T cell-like innate IELs, deciphered their pathway of differentiation and showed their malignant transformation in celiac disease.