Hori Shohei
Laboratory for Immune Homeostasis, RCAI, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Immunol Rev. 2014 May;259(1):159-72. doi: 10.1111/imr.12175.
Regulatory T (Treg) cells expressing the transcription factor forkhead box protein 3 (Foxp3) constitute a unique T-cell lineage committed to suppressive functions. While their differentiation state is remarkably stable in the face of various perturbations from the extracellular environment, they are able to adapt to diverse and fluctuating tissue environments by changing their phenotype. The lineage stability and phenotypic plasticity of Treg cells thus ensure the robustness of self-tolerance and tissue homeostasis. Recent studies have suggested, however, that Treg cells may retain lineage plasticity, the ability to switch their cell fate to various effector T-cell types under certain circumstances such as inflammation, a notion that remains highly contentious. While accumulating evidence indicates that some Treg cells can downregulate Foxp3 expression and/or acquire effector T-helper cell-like phenotypes, results from my laboratory have shown that Treg cells retain epigenetic memory of, and thus remain committed to, Foxp3 expression and suppressive functions despite such phenotypic plasticity. It has also become evident that Foxp3 can be promiscuously and transiently expressed in activated T cells. Here, I argue that the current controversy stems partly from the lack of the lineage specificity of Foxp3 expression and also from the confusion between phenotypic plasticity and lineage plasticity, and discuss implications of our findings in Treg cell fate determination and maintenance.
表达转录因子叉头框蛋白3（Foxp3）的调节性T（Treg）细胞构成了一个独特的致力于抑制功能的T细胞谱系。尽管它们的分化状态在面对细胞外环境的各种干扰时非常稳定，但它们能够通过改变表型来适应多样且波动的组织环境。Treg细胞的谱系稳定性和表型可塑性因此确保了自身耐受性和组织稳态的稳健性。然而，最近的研究表明，Treg细胞可能保留谱系可塑性，即在某些情况下，如炎症时，它们有能力将细胞命运转换为各种效应T细胞类型，这一观点仍然极具争议性。虽然越来越多的证据表明一些Treg细胞可以下调Foxp3表达和/或获得效应性辅助性T细胞样表型，但我实验室的结果表明，尽管有这种表型可塑性，Treg细胞仍保留对Foxp3表达和抑制功能的表观遗传记忆，并因此仍致力于此。同样明显的是，Foxp3可以在活化的T细胞中随机且短暂地表达。在这里，我认为当前的争议部分源于Foxp3表达缺乏谱系特异性，也源于表型可塑性和谱系可塑性之间的混淆，并讨论了我们的发现在Treg细胞命运决定和维持中的意义。
