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A two-amino-acid substitution in the transcription factor RORγt disrupts its function in TH17 differentiation but not in thymocyte development.
Nature Immunology ( IF 27.7 ) Pub Date : 2017-Oct-01 , DOI: 10.1038/ni.3832
Zhiheng He , Jian Ma , Ruiqing Wang , Jing Zhang , Zhaofeng Huang , Fei Wang , Subha Sen , Ellen V Rothenberg , Zuoming Sun

The transcription factor RORγt regulates differentiation of the TH17 subset of helper T cells, thymic T cell development and lymph-node genesis. Although elimination of RORγt prevents TH17 cell-mediated experimental autoimmune encephalomyelitis (EAE), it also disrupts thymocyte development, which could lead to lethal thymic lymphoma. Here we identified a two-amino-acid substitution in RORγt (RORγtM) that 'preferentially' disrupted TH17 differentiation but not thymocyte development. Mice expressing RORγtM were resistant to EAE associated with defective TH17 differentiation but maintained normal thymocyte development and normal lymph-node genesis, except for Peyer's patches. RORγtM showed less ubiquitination at Lys69 that was selectively required for TH17 differentiation but not T cell development. This study will inform the development of treatments that selectively target TH17 cell-mediated autoimmunity but do not affect thymocyte development or induce lymphoma.

中文翻译:

转录因子RORγt中的两个氨基酸取代会破坏其在TH17分化中的功能,但不会破坏胸腺细胞的发育。

转录因子RORγt调节的T分化ħ辅助T细胞,胸腺T细胞的发育和淋巴结成因的17子集。尽管消除RORγt可以预防T H 17细胞介导的实验性自身免疫性脑脊髓炎(EAE),但它也破坏了胸腺细胞的发育,这可能导致致命的胸腺淋巴瘤。在这里,我们在RORγt(RORγt确定两氨基酸替换中号),该“优先”打乱Ť ħ 17分化但不是胸腺细胞发育。小鼠表达RORγt中号是与缺陷相关联的ŤEAE耐ħ 17分化而是维持正常胸腺细胞发育和正常淋巴结成因,除了淋巴集结。RORγtM在Lys69处显示较少的泛素化,这是T H 17分化所必需的,但不是T细胞发育。这项研究将为选择性靶向T H 17细胞介导的自身免疫但不影响胸腺细胞发育或诱发淋巴瘤的治疗方法的开发提供信息。
更新日期:2017-09-07
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