Department of Surgery, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
J Immunol. 2013 Mar 1;190(5):2001-8. doi: 10.4049/jimmunol.1201379. Epub 2013 Jan 28.
FOXP3-expressing T regulatory cells (Tregs) can be divided into two distinct subsets: naturally occurring Tregs (nTregs) that develop in the thymus, and induced Tregs (iTregs) that differentiate in peripheral tissues upon exposure to Ag in a tolerogenic environment. Recently it has been proposed that expression of Helios, an Ikaros family transcription factor, may specifically identify nTregs, allowing specific tracking of Tregs from different origins in health and disease. Surprisingly, we found that Helios(-) cells can be readily identified within naive (CD45RA(+)CD31(+)CCR7(+)CD62L(+)) FOXP3(+) Tregs, a finding inconsistent with the notion that lack of Helios expression identifies Ag-experienced iTregs that should express memory markers. To investigate the phenotype and function of naive Helios(+) and Helios(-) Tregs within the nTreg population, we isolated single-cell clones from each subset. We found that both Helios(+) and Helios(-) nTreg clones have a similar suppressive capacity, as well as expression of FOXP3 and cell surface proteins, including CD39 and CTLA-4. Helios(-) nTregs, however, produced significantly more CCL3 and IFN-γ compared with Helios(+) nTregs. Despite increased cytokine/chemokine production, Helios(-) FOXP3(+) nTreg clones were demethylated at the FOXP3 Treg-specific demethylated region, indicative of Treg lineage stability. When cultured under Th1-polarizing conditions, Helios(+) and Helios(-) nTreg clones had an equal ability to produce IFN-γ. Collectively, these data show that a lack of Helios expression does not exclusively identify human iTregs, and, to our knowledge, the data provide the first evidence for the coexistence of Helios(+) and Helios(-) nTregs in human peripheral blood.
叉头框蛋白 P3（FOXP3）表达的调节性 T 细胞（Tregs）可分为两个不同的亚群：在胸腺中发育的天然存在的调节性 T 细胞（nTregs），以及在外周组织中分化的诱导性调节性 T 细胞（iTregs），当它们在耐受环境中遇到抗原时。最近有人提出，转录因子 Helios 的表达可能专门识别 nTregs，从而允许在健康和疾病中对来自不同来源的 Tregs 进行特异性跟踪。令人惊讶的是，我们发现 Helios(-)细胞可以在幼稚（CD45RA(+)CD31(+)CCR7(+)CD62L(+)）FOXP3(+)Tregs 中轻易识别，这一发现与缺乏 Helios 表达识别经历过抗原的 iTregs 的观点不一致，因为 iTregs 应该表达记忆标志物。为了研究幼稚 Helios(+)和 Helios(-)Tregs 在 nTreg 群体中的表型和功能，我们从每个亚群中分离出单细胞克隆。我们发现，Helios(+)和 Helios(-)nTreg 克隆都具有相似的抑制能力，以及 FOXP3 和细胞表面蛋白的表达，包括 CD39 和 CTLA-4。然而，Helios(-)nTregs 产生的 CCL3 和 IFN-γ 明显多于 Helios(+)nTregs。尽管细胞因子/趋化因子的产生增加，但 Helios(-)FOXP3(+)nTreg 克隆在 FOXP3 Treg 特异性去甲基化区域被去甲基化，表明 Treg 谱系的稳定性。当在 Th1 极化条件下培养时，Helios(+)和 Helios(-)nTreg 克隆产生 IFN-γ 的能力相等。总的来说，这些数据表明缺乏 Helios 表达并不完全识别人类 iTregs，并且据我们所知，这些数据首次提供了人类外周血中存在 Helios(+)和 Helios(-)nTregs 的证据。
