Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development
Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development
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DOI：
10.1073/pnas.0509484103
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发表时间：
2006-04-25
影响因子：
11.1
通讯作者：
Rudensky, AY
中科院分区：
文献类型：
--
作者：
Gavin, MA;Torgerson, TR;Rudensky, AY
叉头状翼螺旋转录因子Foxp 3是调控小鼠CD 25（+）CD 4（+）调节性T细胞（TR）发育和功能的遗传程序的专用介质。在人类中，它在介导TR发育中的作用一直存在争议。此外，T-R前体在FOXP 3缺陷中的命运尚未被描述。利用流式细胞术检测人FOXP 3，我们已经解决了FOXP 3的表达和人类TR的发展之间的关系。与鼠Foxp 3（-）T细胞不同，一小部分人CD 4（+）和CD 8（+）T细胞在体外刺激时瞬时上调FOXP 3。然而，诱导FOXP 3并不改变细胞表面表型或抑制T辅助细胞1细胞因子的表达。此外，只有离体FOXP 3（+）TR细胞在长时间培养后仍然存在，表明诱导的FOXP 3在大量细胞中没有激活TR发育程序。FOXP 3流式细胞术还用于进一步表征表现出免疫失调、多内分泌病、肠病、X连锁综合征（IPEX）（有或没有FOXP 3突变）症状的几个患者。大多数患者缺乏FOXP 3表达细胞，进一步巩固了FOXP 3缺陷与免疫失调、多内分泌病、肠病、X连锁综合征之间的关联。有趣的是，一名携带FOXP 3突变的患者能够表达稳定的FOXP 3（mut）蛋白，在高度活化的CD 4（+）T细胞亚群中显示FOXP 3（mut）表达细胞。这一观察结果提出了一种可能性，即FOXP 3缺乏症中的严重自身免疫性可以部分归因于从TR前体发展而来的侵袭性T辅助细胞。
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.