Single-Cell Analysis of the Human T Regulatory Population Uncovers Functional Heterogeneity and Instability within FOXP3+ Cells
Single-Cell Analysis of the Human T Regulatory Population Uncovers Functional Heterogeneity and Instability within FOXP3+ Cells
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DOI：
10.4049/jimmunol.1100269
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发表时间：
2011-06-15
影响因子：
4.4
通讯作者：
Piccirillo, Ciriaco A.
中科院分区：
文献类型：
--
作者：
d'Hennezel, Eva;Yurchenko, Ekaterina;Piccirillo, Ciriaco A.
天然FOXP3(+)CD4(+)CD25（高）调节性T细胞在免疫自我耐受中起关键作用。由于在炎症中无法将这些细胞与激活的效应T细胞区分开来，它们在人类中的表征受到阻碍。为了在克隆水平上探索FOXP3表达与调控功能之间的关系，我们使用了来自健康人类供体的表达cd25的CD4(+) T细胞亚群的单细胞克隆策略。我们的方法揭示了嵌套在CD4(+)CD25(High)FOXP3(+) T细胞中的功能异质性，这通常是传统的批量检测所无法揭示的。尽管大多数细胞表现出典型调节性T （T- reg）细胞特征，但很大一部分FOXP3(+) T细胞的抑制功能受到损害，尽管维持了其他表型和功能调节性T标志特征。此外，这些非抑制性FOXP3(+) T细胞优先出现在CD45RO（+）记忆池中，并且在T细胞再激活时FOXP3表达快速下调。令人惊讶的是，这些功能失调的T-REG细胞FOXP3表达不稳定，在炎症细胞因子分泌方面没有明显的可塑性。这些结果为广泛研究CD4(+)CD25（高）FOXP3(+) T-REG细胞的功能异质性开辟了道路，并且在单独使用FOXP3作为监测人类免疫调节的临床标志物时需要谨慎。中华免疫学杂志，2011,26(6):688 - 697。
Natural FOXP3(+)CD4(+)CD25(High) regulatory T cells are critical in immunological self-tolerance. Their characterization in humans is hindered by the failure to discriminate these cells from activated effector T cells in inflammation. To explore the relationship between FOXP3 expression and regulatory function at the clonal level, we used a single-cell cloning strategy of CD25-expressing CD4(+) T cell subsets from healthy human donors. Our approach unveils a functional heterogeneity nested within CD4(+)CD25(High)FOXP3(+) T cells, and typically not revealed by conventional bulk assays. Whereas most cells display the canonical regulatory T (T-REG) cell characteristics, a significant proportion of FOXP3(+) T cells is compromised in its suppressive function, despite the maintenance of other phenotypic and functional regulatory T hallmark features. In addition, these nonsuppressive FOXP3(+) T cells preferentially emerge from the CD45RO(+) memory pool, and arise as a consequence of a rapid downregulation of FOXP3 expression upon T cell reactivation. Surprisingly, these dysfunctional T-REG cells with unstable FOXP3 expression do not manifest overt plasticity in terms of inflammatory cytokine secretion. These results open a path to an extensive study of the functional heterogeneity of CD4(+)CD25(High)FOXP3(+) T-REG cells and warrant caution in the sole use of FOXP3 as a clinical marker for monitoring of immune regulation in humans. The Journal of Immunology, 2011, 186: 6788-6797.