Iron capture through CD71 dictates perinatal and tumoral Treg expansion modulating iron homeostasis and gut microbiota colonization

Beside suppressing immune responses, regulatory T cells (Tregs) maintain tissue homeostasis and control systemic metabolism. Whether iron, a fundamental element for all living cells, is required for Treg expansion, is completely unknown. Here, we showed that the transferrin receptor CD71 was upregulated on activated proliferating Tregs infiltrating human liver cancer. Mice with a Treg-restricted CD71 deficiency spontaneously developed a scurfy-like disease, caused by a severe impairment in perinatal Treg expansion. CD71-null Tregs display decreased proliferation and mitochondrial functions, and a tissue-Treg signature loss. In the perinatal life, CD71 deficiency in Tregs triggered a hepatic response to iron overload, characterized by increased hepcidin transcription and iron accumulation in macrophages. A lower bacterial diversity, and a reduction of beneficial species, were detected in the faecal microbiota of CD71 conditional knock-out neonates. Our findings indicate that the CD71-mediated iron absorption is required for Treg perinatal expansion and controls the systemic iron homeostasis, which in turn shapes the bacterial gut colonization. Comparative gene expression profiling analysis of RNA-seq data for sorted CD4+ YFP+ Tregs from splenocytes of Foxp3Cre/+ Tfrcfl/fl and Foxp3Cre/+ Tfrc+/+ female mice

除抑制免疫应答外，调节性T细胞（regulatory T cells, Tregs）还可维持组织稳态并调控全身代谢。铁作为所有活细胞的必需基础元素，其是否为Tregs扩增所必需，目前尚完全未知。本研究发现，浸润人类肝癌组织的活化增殖性Tregs中，转铁蛋白受体CD71表达上调。Tregs特异性缺失CD71的小鼠会自发出现Scurfy综合征样疾病，其致病机制为围产期Tregs扩增出现严重缺陷。CD71缺失的Tregs表现出增殖能力下降、线粒体功能受损，以及组织特异性Treg特征的丢失。在围产期，Tregs中CD71缺失会触发肝脏针对铁过载的应答，具体表现为铁调素转录水平升高以及巨噬细胞内铁蓄积。在CD71条件性敲除新生小鼠的粪便菌群中，可检测到细菌多样性降低、有益菌种丰度下降。本研究结果表明，CD71介导的铁摄取过程是围产期Tregs扩增所必需的，并可调控全身铁稳态，进而塑造肠道菌群的定植模式。本研究对来自Foxp3Cre/+ Tfrcfl/fl与Foxp3Cre/+ Tfrc+/+雌性小鼠脾细胞中分选得到的CD4+ 黄色荧光蛋白（yellow fluorescent protein, YFP）阳性Tregs的RNA测序（RNA-seq）数据开展了比较基因表达谱分析。