Brunk Fabian, Augustin Iris, Meister Michael, Boutros Michael, Kyewski Bruno
Division of Developmental Immunology, Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany;
Division of Signaling and Functional Genomics, German Cancer Research Center, Heidelberg, 69120 Germany; Department of Cell and Molecular Biology, Faculty of Medicine Mannheim, Heidelberg University, 68167 Heidelberg, Germany; and.
J Immunol. 2015 Dec 1;195(11):5261-71. doi: 10.4049/jimmunol.1501265. Epub 2015 Oct 28.
Wnt signaling has been implicated in T cell development. However, it remained unclear which cell type is the major source of Wnt ligands and to what extent thymic epithelial cell (TEC) development is dependent on Wnt signaling. In this study, we analyzed the role of Wnt ligands provided by TECs for the development of T cells and TECs without manipulating the intracellular Wnt signaling machinery in either cell type. To this end, we used conditional knockout mice (FoxN1-Gpr177) in which TECs are unable to secrete Wnt ligands. Gpr177 (Evi/Wls) is a Wnt-specific cargo receptor that is required for the secretion of Wnt ligands. We found that TECs are the main source of Wnt ligands in the thymus, which serves a nonredundant role, and lack of TEC-provided Wnt ligands led to thymic hypotrophy, as well as a reduced peripheral T cell pool. Despite being reduced in numbers, T cells that developed in the absence of TEC-secreted Wnt ligands were functionally competent, and the subset composition of the peripheral T cell pool was not affected. Thus, our data suggest that T cell development is not directly dependent on TEC-provided Wnt ligands. Rather, TEC-secreted Wnt ligands are essential for normal thymus development and normal peripheral T cell frequencies but are dispensable for T cell function in the periphery.
Wnt信号通路与T细胞发育有关。然而，尚不清楚哪种细胞类型是Wnt配体的主要来源，以及胸腺上皮细胞（TEC）的发育在多大程度上依赖于Wnt信号通路。在本研究中，我们分析了TEC提供的Wnt配体对T细胞和TEC发育的作用，而不操纵任何一种细胞类型的细胞内Wnt信号机制。为此，我们使用了条件性敲除小鼠（FoxN1-Gpr177），其中TEC无法分泌Wnt配体。Gpr177（Evi/Wls）是一种Wnt特异性货物受体，是Wnt配体分泌所必需的。我们发现TEC是胸腺中Wnt配体的主要来源，发挥着非冗余作用，缺乏TEC提供的Wnt配体导致胸腺萎缩以及外周T细胞库减少。尽管数量减少，但在没有TEC分泌的Wnt配体的情况下发育的T细胞功能正常，并且外周T细胞库的亚群组成不受影响。因此，我们的数据表明T细胞发育并不直接依赖于TEC提供的Wnt配体。相反，TEC分泌的Wnt配体对于正常胸腺发育和正常外周T细胞频率至关重要，但对于外周T细胞功能来说并非必需。
