A function for interleukin 2 in Foxp3-expressing regulatory T cells

Regulatory T cells (Treg cells) expressing the forkhead family transcription factor Foxp3 are critical mediators of dominant immune tolerance to self. Most Treg cells constitutively express the high-affinity interleukin 2 (IL-2) receptor alpha-chain (CD25); however, the precise function of IL-2 in Treg cell biology has remained controversial. To directly assess the effect of IL-2 signaling on Treg cell development and function, we analyzed mice containing the Foxp3gfp knock-in allele that were genetically deficient in either IL-2 (Il2-/-) or CD25 (Il2ra-/-). We found that IL-2 signaling was dispensable for the induction of Foxp3 expression in thymocytes from these mice, which indicated that IL-2 signaling does not have a nonredundant function in the development of Treg cells. Unexpectedly, Il2-/- and Il2ra-/- Treg cells were fully able to suppress T cell proliferation in vitro. In contrast, Foxp3 was not expressed in thymocytes or peripheral T cells from Il2rg-/- mice. Gene expression analysis showed that IL-2 signaling was required for maintenance of the expression of genes involved in the regulation of cell growth and metabolism. Thus, IL-2 signaling seems to be critically required for maintaining the homeostasis and competitive fitness of Treg cells in vivo. Keywords: cell type comparison We isolated Foxp3+ CD4+ T cells from Il2-/- mice treated with PBS or recombinant IL-2 for gene expression analysis using whole-genome oligonucleotide microarrays. To identify gene expression changes resulting from IL-2 deficiency and subsequent IL-2 stimulation in Treg cells, we directly compared expression profiles with each other and with expression profiles of Foxp3+ CD4+ T cells isolated from wild-type mice.

表达叉头框家族转录因子Foxp3的调节性T细胞（Regulatory T cells, Treg cells）是介导自身显性免疫耐受的关键介质。绝大多数Treg细胞组成性表达高亲和力白细胞介素2（interleukin 2, IL-2）受体α链（CD25）；然而，IL-2在Treg细胞生物学中的确切功能始终存在争议。
为直接评估IL-2信号通路对Treg细胞发育与功能的影响，我们对携带Foxp3gfp敲入等位基因、且分别存在IL-2（Il2-/-）或CD25（Il2ra-/-）基因缺陷的小鼠开展了分析。研究发现，IL-2信号通路对于上述小鼠胸腺细胞中Foxp3的表达诱导并非必需，这表明IL-2信号通路在Treg细胞发育过程中并不具备非冗余功能。
出乎意料的是，Il2-/-与Il2ra-/-小鼠的Treg细胞在体外仍可完全抑制T细胞增殖。
与之相反，Il2rg-/-小鼠的胸腺细胞及外周T细胞均不表达Foxp3。
基因表达分析结果显示，IL-2信号通路是维持细胞生长与代谢调控相关基因表达所必需的。
由此可见，IL-2信号通路在体内维持Treg细胞稳态与竞争适配性方面发挥关键作用。
关键词：细胞类型比较
我们采用全基因组寡核苷酸微阵列技术，对经磷酸盐缓冲液（phosphate buffered saline, PBS）或重组IL-2处理的Il2-/-小鼠体内分离得到的Foxp3+ CD4+ T细胞进行基因表达分析。为明确Treg细胞中因IL-2缺失及后续IL-2刺激所引发的基因表达变化，我们将各组表达谱进行了相互比较，并与野生型小鼠分离得到的Foxp3+ CD4+ T细胞表达谱进行了对比。