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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development
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Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development

机译：正常和FOXP3突变型人类T细胞的单细胞分析：FOXP3表达而无需调节性T细胞发育

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摘要

Forkhead winged-helix transcription factor Foxp3 serves as the dedicated mediator of the genetic program governing CD25(+)CD4(+) regulatory T cell (TR) development and function in mice. In humans, its role in mediating TR development has been controversial. Furthermore, the fate of T-R precursors in FOXP3 deficiency has yet to be described. Making use of flow cytometric detection of human FOXP3, we have addressed the relationship between FOXP3 expression and human TR development. Unlike murine Foxp3(-) T cells, a small subset of human CD4(+) and CD8(+) T cells transiently upregulated FOXP3 upon in vitro stimulation. Induced FOXP3, however, did not alter cell-surface phenotype or suppress T helper 1 cytokine expression. Furthermore, only ex vivo FOXP3(+) TR cells persisted after prolonged culture, suggesting that induced FOXP3 did not activate a TR developmental program in a significant number of cells. FOXP3 flow cytometry was also used to further characterize several patients exhibiting symptoms of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) with or without FOXP3 mutations. Most patients lacked FOXP3-expressing cells, further solidifying the association between FOXP3 deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Interestingly, one patient bearing a FOXP3 mutation enabling expression of stable FOXP3(mut) protein exhibited FOXP3(mut)-expressing cells among a subset of highly activated CD4(+) T cells. This observation raises the possibility that the severe autoimmunity in FOXP3 deficiency can be attributed, in part, to aggressive T helper cells that have developed from TR precursors.
机译：前叉有翼螺旋转录因子Foxp3充当遗传程序的专门介导者，可在小鼠中控制CD25（+）CD4（+）调节性T细胞（TR）的发育和功能。在人类中，其在介导TR发育中的作用一直存在争议。此外，尚未描述FOXP3缺乏症中T-R前体的命运。利用人类FOXP3的流式细胞仪检测，我们解决了FOXP3表达与人类TR发育之间的关系。与鼠Foxp3（-）T细胞不同，一小部分人CD4（+）和CD8（+）T细胞在体外刺激后会瞬时上调FOXP3。但是，诱导的FOXP3不会改变细胞表面表型或抑制T辅助1细胞因子的表达。此外，长时间的培养后，只有离体的FOXP3（+）TR细胞仍然存在，这表明诱导的FOXP3并未激活大量细胞中的TR发育程序。 FOXP3流式细胞仪还用于进一步表征几例出现免疫失调，多内分泌病，肠病，X连锁综合征（IPEX）的患者，这些患者有或没有FOXP3突变。大多数患者缺乏表达FOXP3的细胞，从而进一步巩固了FOXP3缺乏与免疫失调，多内分泌病，肠病，X连锁综合症之间的联系。有趣的是，一名携带FOXP3突变并能够表达稳定的FOXP3（mut）蛋白的患者在高活化CD4（+）T细胞子集中显示了FOXP3（mut）表达细胞。该观察结果提出了以下可能性：FOXP3缺乏症的严重自身免疫可部分归因于从TR前体形成的侵袭性T辅助细胞。

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