IL-2 receptor β-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells

IL-2(-/-) mice develop autoimmunity despite having relatively normal numbers of regulatory T cells (Tregs). In contrast, we demonstrate that IL-2(-/-) X IL-15(-/-) and IL-2R beta(-/-) mice have a significant decrease in Treg numbers. Ectopic expression of foxp3 in a subset of CD4(+) T cells rescued Treg development and prevented autoimmunity in IL-2R beta(-/-) mice, suggesting that IL-2R beta-dependent signals regulate foxp3 expression in Tregs. Subsequent analysis of IL-2R beta-dependent signal transduction pathways established that the transcription factor STAT5 is necessary and sufficient for Treg development. Specifically, T cell-specific deletion of STAT5 prevented Treg development; conversely, reconstitution of IL-2R beta(-/-) mice with bone marrow cells expressing an IL-2R beta mutant that exclusively activates STAT5 restored Treg development. Finally, STAT5 binds to the promoter of the foxp3 gene suggesting that IL-2R beta-dependent STAT5 activation promotes Treg differentiation by regulating expression of foxp3.

白细胞介素 - 2（IL - 2）基因敲除（- / -）小鼠尽管调节性T细胞（Tregs）数量相对正常，但仍会发生自身免疫。相比之下，我们发现白细胞介素 - 2（IL - 2）和白细胞介素 - 15（IL - 15）双基因敲除（- / -）以及白细胞介素 - 2受体β（IL - 2Rβ）基因敲除（- / -）小鼠的调节性T细胞数量显著减少。在一部分CD4⁺T细胞中异位表达foxp3可挽救调节性T细胞的发育，并防止白细胞介素 - 2受体β（IL - 2Rβ）基因敲除小鼠发生自身免疫，这表明白细胞介素 - 2受体β依赖的信号调节调节性T细胞中foxp3的表达。对白细胞介素 - 2受体β依赖的信号转导通路的后续分析证实，转录因子STAT5对调节性T细胞的发育是必要且充分的。具体而言，T细胞特异性缺失STAT5会阻止调节性T细胞的发育；相反，用表达一种仅激活STAT5的白细胞介素 - 2受体β突变体的骨髓细胞对白细胞介素 - 2受体β（IL - 2Rβ）基因敲除小鼠进行重建，可恢复调节性T细胞的发育。最后，STAT5与foxp3基因的启动子结合，这表明白细胞介素 - 2受体β依赖的STAT5激活通过调节foxp3的表达来促进调节性T细胞的分化。