Cytokine receptor modulation by interleukin-2 broadly regulates T helper cell lineage differentiation. Cytokine receptor modulation by interleukin-2 broadly regulates T helper cell lineage differentiation

T helper (Th) cells control host defense to pathogens. IL 12R expression is required for Th1, IL-4Rα for Th2, and IL-6Rα/gp130 for Th17 differentiation to allow responsiveness to IL-12, IL-4, and IL-6, respectively. IL-2 via STAT5 controls Th2 differentiation by regulating the Th2 cytokine gene cluster and Il4ra expression. Here we show that IL-2 regulates Th1 differentiation, inducing STAT5-dependent IL-12Rβ2 and T-bet expression, with impaired human Th1 differentiation when IL-2 was blocked. Th1 differentiation was also impaired in mouse Il2-/- T cells but restored by IL-12Rβ2 expression. Consistent with IL-2’s inhibition of Th17 differentiation, IL-2 decreased Il6ra and Il6st/gp130 expression, and Il6st augmented Th17 differentiation even when IL-2 was present. Thus, IL-2 influences T-cell differentiation by modulating cytokine receptor expression to help specify/maintain differentiated states. Overall design: Genome-wide mapping of STAT1,STAT4,STAT5A,STAT5B binding to their target genes in Th1 or human CD4+ cells was conducted

T辅助细胞（T helper, Th）调控宿主对病原体的免疫防御。
白细胞介素12受体（Interleukin-12 receptor, IL-12R）的表达是Th1细胞分化的必要条件，白细胞介素4受体α链（Interleukin-4 receptor alpha, IL-4Rα）为Th2细胞分化所必需，而白细胞介素6受体α/糖蛋白130（Interleukin-6 receptor alpha/glycoprotein 130, IL-6Rα/gp130）则是Th17细胞分化的必需因子，分别使细胞获得对IL-12、IL-4及IL-6的响应能力。
白细胞介素2（Interleukin-2, IL-2）可通过信号转导与转录激活因子5（Signal transducer and activator of transcription 5, STAT5）调控Th2细胞分化，具体机制为调控Th2细胞因子基因簇及Il4ra的表达。
本研究发现，IL-2还可调控Th1细胞分化：其可诱导STAT5依赖性的IL-12Rβ2（白细胞介素12受体β2链，Interleukin-12 receptor beta2, IL-12Rβ2）及T-bet（T-box转录因子21，T-box transcription factor 21）的表达；当IL-2被阻断时，人类Th1细胞的分化会受到损伤。
在Il2基因敲除（Il2-/-）的小鼠T细胞中，Th1分化同样存在缺陷，而通过过表达IL-12Rβ2可修复该缺陷。
与IL-2抑制Th17细胞分化的结论一致，IL-2可下调Il6ra及Il6st/gp130的表达；即便存在IL-2，Il6st的过表达仍可增强Th17细胞的分化能力。
综上，IL-2通过调控细胞因子受体的表达参与T细胞分化调控，以帮助确立并维持细胞的分化状态。
实验总体设计：本研究针对STAT1、STAT4、STAT5A及STAT5B在Th1细胞或人类CD4+ T细胞中与靶基因的结合情况，开展了全基因组结合位点图谱分析。