RET/GFRα Signals Are Dispensable for Thymic T Cell Development In Vivo

Identification of thymocyte regulators is a central issue in T cell biology. Interestingly, growing evidence indicates that common key molecules control neuronal and immune cell functions. The neurotrophic factor receptor RET mediates critical functions in foetal hematopoietic subsets, thus raising the possibility that RET-related molecules may also control T cell development. We show that Ret, Gfra1 and Gfra2 are abundantly expressed by foetal and adult immature DN thymocytes. Despite the developmentally regulated expression of these genes, analysis of foetal thymi from Gfra1, Gfra2 or Ret deficient embryos revealed that these molecules are dispensable for foetal T cell development. Furthermore, analysis of RET gain of function and Ret conditional knockout mice showed that RET is also unnecessary for adult thymopoiesis. Finally, competitive thymic reconstitution assays indicated that Ret deficient thymocytes maintained their differentiation fitness even in stringent developmental conditions. Thus, our data demonstrate that RET/GFRα signals are dispensable for thymic T cell development in vivo, indicating that pharmacological targeting of RET signalling in tumours is not likely to result in T cell production failure.

胸腺细胞调控因子的鉴定是T细胞生物学领域的核心议题之一。有趣的是，越来越多的研究证据表明，共有关键分子可同时调控神经元与免疫细胞的功能。神经营养因子受体RET（RET）能够介导胎儿造血细胞亚群的关键生物学功能，这提示RET相关分子或许也参与调控T细胞发育过程。本研究证实，Ret、Gfra1与Gfra2在胎儿及成体未成熟双阴性（DN）胸腺细胞中均呈高表达水平。尽管这些基因的表达受发育进程精准调控，但对Gfra1、Gfra2或Ret基因缺陷胚胎的胎儿胸腺进行分析后发现，上述分子对于胎儿T细胞发育并非必需。此外，通过对RET功能获得性突变小鼠以及Ret条件性敲除小鼠的分析显示，RET对于成体胸腺细胞发生同样并非必需。最后，竞争性胸腺重建实验结果表明，即便处于严苛的发育环境中，Ret缺陷胸腺细胞仍可维持其分化适配能力。综上，本研究数据证实，RET/胶质细胞源性神经营养因子受体α（GFRα）信号通路对于体内胸腺内T细胞发育并非必需，这意味着针对肿瘤中RET信号通路的靶向药理学治疗，不太可能引发T细胞生成障碍。