Fontenot Jason D, Rasmussen Jeffrey P, Gavin Marc A, Rudensky Alexander Y
Howard Hughes Medical Institute, Department of Immunology, University of Washington, Seattle, Washington 98195, USA.
Nat Immunol. 2005 Nov;6(11):1142-51. doi: 10.1038/ni1263. Epub 2005 Oct 16.
Regulatory T cells (T(reg) cells) expressing the forkhead family transcription factor Foxp3 are critical mediators of dominant immune tolerance to self. Most T(reg) cells constitutively express the high-affinity interleukin 2 (IL-2) receptor alpha-chain (CD25); however, the precise function of IL-2 in T(reg) cell biology has remained controversial. To directly assess the effect of IL-2 signaling on T(reg) cell development and function, we analyzed mice containing the Foxp3(gfp) 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 T(reg) cells. Unexpectedly, Il2(-/-) and Il2ra(-/-) T(reg) 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 T(reg) cells in vivo.
表达叉头家族转录因子Foxp3的调节性T细胞（Treg细胞）是机体对自身产生显性免疫耐受的关键介质。大多数Treg细胞组成性表达高亲和力白细胞介素2（IL-2）受体α链（CD25）；然而，IL-2在Treg细胞生物学中的精确功能仍存在争议。为了直接评估IL-2信号对Treg细胞发育和功能的影响，我们分析了携带Foxp3（gfp）基因敲入等位基因且在IL-2（Il2-/-）或CD25（Il2ra-/-）基因上存在遗传缺陷的小鼠。我们发现，IL-2信号对于诱导这些小鼠胸腺细胞中Foxp3的表达并非必需，这表明IL-2信号在Treg细胞发育过程中没有不可替代的功能。出乎意料的是，Il2-/-和Il2ra-/- Treg细胞在体外完全能够抑制T细胞增殖。相比之下，Il2rg-/-小鼠的胸腺细胞或外周T细胞中不表达Foxp3。基因表达分析表明，IL-2信号对于维持参与细胞生长和代谢调节的基因表达是必需的。因此，IL-2信号似乎对于维持体内Treg细胞的稳态和竞争适应性至关重要。
