Dominant Th2 Differentiation of Human Regulatory T Cells upon Loss of FOXP3 Expression
Dominant Th2 Differentiation of Human Regulatory T Cells upon Loss of FOXP3 Expression
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DOI：
10.4049/jimmunol.1102288
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发表时间：
2012-02-01
影响因子：
4.4
通讯作者：
Edinger, Matthias
中科院分区：
文献类型：
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作者：
Hansmann, Leo;Schmidl, Christian;Edinger, Matthias
CD4(+)CD25(+)FOXP3（+）调节性T细胞（Treg）是外周自我耐受的关键。它们可以防止对自身抗原和同种异体抗原的免疫反应，因此作为自身免疫性疾病的细胞疗法和器官或干细胞移植后的同种异体反应的预防或治疗受到密切关注。我们之前的研究表明，具有记忆细胞表型的人类Treg，而不是具有幼稚表型的Treg，在体外扩增后迅速下调谱系定义转录因子FOXP3的表达。我们现在比较了稳定的FOXP3(+) Treg和转化的FOXP3(-) ex-Treg的转录组，采用了一种新开发的核内染色方案，该方案允许从固定的、渗透的和facs纯化的细胞群体中分离完整的mRNA。全基因组微阵列分析显示，在FOXP3下调的同时，Th2的特征基因GATA-3、IL-4、IL-5和IL-13也有强烈的选择性上调。即使在非极化条件下，转化的FOXP3(-) ex-Treg的Th2分化也会发生，并且IL-4信号阻断无法阻止。因此，我们的研究发现，在FOXP3下调后，Th2分化是人类Treg的默认发育程序。免疫学杂志，2012,18(8):1275-1282。
CD4(+)CD25(+)FOXP3(+) regulatory T cells (Treg) are pivotal for peripheral self-tolerance. They prevent immune responses to auto- and alloantigens and are thus under close scrutiny as cellular therapeutics for autoimmune diseases and the prevention or treatment of alloresponses after organ or stem cell transplantation. We previously showed that human Treg with a memory cell phenotype, but not those with a naive phenotype, rapidly downregulate expression of the lineage-defining transcription factor FOXP3 upon in vitro expansion. We now compared the transcriptomes of stable FOXP3(+) Treg and converted FOXP3(-) ex-Treg by applying a newly developed intranuclear staining protocol that permits the isolation of intact mRNA from fixed, permeabilized, and FACS-purified cell populations. Whole-genome microarray analysis revealed strong and selective upregulation of Th2 signature genes, including GATA-3, IL-4, IL-5, and IL-13, upon downregulation of FOXP3. Th2 differentiation of converted FOXP3(-) ex-Treg occurred even under nonpolarizing conditions and could not be prevented by IL-4 signaling blockade. Thus, our studies identify Th2 differentiation as the default developmental program of human Treg after downregulation of FOXP3. The Journal of Immunology, 2012, 188: 1275-1282.