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FoxP3 scanning mutagenesis reveals functional variegation and mild mutations with atypical autoimmune phenotypes
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2018-01-09 00:00:00 , DOI: 10.1073/pnas.1718599115
Ho-Keun Kwon 1, 2 , Hui-Min Chen 1, 2 , Diane Mathis 1, 2 , Christophe Benoist 1, 2
Affiliation  

FoxP3+ regulatory T cells (Tregs) are a central element of immunological tolerance. FoxP3 is the key determining transcription factor of the Treg lineage, interacting with numerous cofactors and transcriptional targets to determine the many facets of Treg function. Its absence leads to devastating lymphoproliferation and autoimmunity in scurfy mutant mice and immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) patients. To finely map transcriptionally active regions of the protein, with respect to disease-causing variation, we performed a systematic alanine-scan mutagenesis of FoxP3, assessing mutational impacts on DNA binding and transcriptional activation or repression. The mutations affected transcriptional activation and repression in a variegated manner involving multiple regions of the protein and varying between different transcriptional targets of FoxP3. There appeared to be different modalities for target genes related to classic immunosuppressive function vs. those related to atypical or tissue-Treg functions. Relevance to in vivo Treg biology was established by introducing some of the subtle Foxp3 mutations into the mouse germline by CRISPR-based genome editing. The resulting mice showed Treg populations in normal numbers and exhibited no overt autoimmune manifestations. However, Treg functional defects were revealed upon competition or by system stress, manifest as a strikingly heightened susceptibility to provoked colitis, and conversely by greater resistance to tumors. These observations suggest that some of the missense mutations that segregate in human populations, but do not induce IPEX manifestations, may have unappreciated consequences in other diseases.

中文翻译:

FoxP3扫描诱变显示具有非典型自身免疫表型的功能变异和轻度突变

FoxP3 +调节性T细胞(Tregs)是免疫耐受的重要组成部分。FoxP3是确定Treg谱系转录因子的关键,它与众多辅助因子和转录靶标相互作用,以确定Treg功能的许多方面。它的缺乏会导致坏死的淋巴细胞增殖和自身免疫突变小鼠和免疫调节异常的多内分泌病性肠病X连锁(IPEX)患者。为了精确地映射蛋白质的转录活性区域(关于致病变异),我们进行了FoxP3的系统丙氨酸扫描诱变,评估了突变对DNA结合和转录激活或抑制的影响。突变以多种方式影响转录激活和抑制,涉及蛋白质的多个区域,并且在FoxP3的不同转录靶之间变化。与经典免疫抑制功能相关的靶基因与与非典型或组织Treg功能相关的靶基因似乎存在不同的模式。通过引入一些微妙的Foxp3建立了与体内Treg生物学的相关性通过基于CRISPR的基因组编辑将突变导入小鼠种系。所得小鼠显示正常数量的Treg种群,并且没有明显的自身免疫表现。但是,Treg的功能缺陷是在竞争或系统压力时揭示的,表现为对诱发性结肠炎的敏感性显着提高,反之则对肿瘤的抵抗力更大。这些观察结果表明,某些在人类群体中隔离但不诱导IPEX表现的错义突变可能在其他疾病中产生无法估量的后果。
更新日期:2018-01-10
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