Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland.
Blood. 2010 Jun 3;115(22):4431-8. doi: 10.1182/blood-2009-11-254698. Epub 2010 Mar 22.
The murine gut epithelium contains a large population of thymus-derived intraepithelial lymphocytes (IELs), including both conventional CD4(+) and CD8alphabeta(+) T cells (expressing T-cell receptor alphabeta [TCRalphabeta]) and unconventional CD8alphaalpha(+) T cells (expressing either TCRalphabeta or TCRgammadelta). Whereas conventional IELs are widely accepted to arise from recirculation of activated CD4(+) and CD8alphabeta(+) T cells from the secondary lymphoid organs to the gut, the origin and developmental pathway of unconventional CD8alphaalpha IELs remain controversial. We show here that CD4-Cre-mediated inactivation of c-Myc, a broadly expressed transcription factor with a wide range of biologic activities, selectively impairs the development of CD8alphaalpha TCRalphabeta IELs. In the absence of c-Myc, CD4(-) CD8(-) TCRalphabeta(+) thymic precursors of CD8alphaalpha TCRalphabeta IELs are present but fail to develop on adoptive transfer in immunoincompetent hosts. Residual c-Myc-deficient CD8alphaalpha TCRalphabeta IEL display reduced proliferation and increased apoptosis, which correlate with significantly decreased expression of interleukin-15 receptor subunits and lower levels of the antiapoptotic protein Bcl-2. Transgenic overexpression of human BCL-2 resulted in a pronounced rescue of CD8alphaalpha TCRalphabeta IEL in c-Myc-deficient mice. Taken together, our data support a model in which c-Myc controls the development of CD8alphaalpha TCRalphabeta IELs from thymic precursors by regulating interleukin-15 receptor expression and consequently Bcl-2-dependent survival.
鼠类肠道上皮含有大量的胸腺衍生的上皮内淋巴细胞（IELs），包括常规的 CD4(+) 和 CD8alphabeta(+) T 细胞（表达 T 细胞受体 alpha/beta [TCRalphabeta]）和非常规的 CD8alphaalpha(+) T 细胞（表达 TCRalphabeta 或 TCRgammadelta）。虽然常规 IEL 被广泛认为是从次级淋巴器官循环到肠道的激活的 CD4(+) 和 CD8alphabeta(+) T 细胞产生的，但是非常规 CD8alphaalpha IEL 的起源和发育途径仍然存在争议。我们在这里表明，CD4-Cre 介导的广泛表达的转录因子 c-Myc 的失活，具有广泛的生物学活性，选择性地损害了 CD8alphaalpha TCRalphabeta IEL 的发育。在没有 c-Myc 的情况下，CD4(-) CD8(-) TCRalphabeta(+) CD8alphaalpha TCRalphabeta IEL 的胸腺前体存在，但在免疫无能宿主的过继转移中未能发育。残留的 c-Myc 缺陷型 CD8alphaalpha TCRalphabeta IEL 显示出减少的增殖和增加的凋亡，这与白细胞介素-15 受体亚基表达显著降低和抗凋亡蛋白 Bcl-2 水平降低相关。人 BCL-2 的转基因过表达导致 c-Myc 缺陷型小鼠中 CD8alphaalpha TCRalphabeta IEL 的明显挽救。综上所述，我们的数据支持这样一种模型，即 c-Myc 通过调节白细胞介素-15 受体的表达并因此调节 Bcl-2 依赖性存活来控制来自胸腺前体的 CD8alphaalpha TCRalphabeta IEL 的发育。
