The type 2 cytokines, interleukin (IL)-4, IL-13 and IL-5 reside within a multigene cluster. Both innate (ILC2) and adaptive T helper 2 (T_H2) lymphocytes secrete type 2 cytokines with diverse production spectra. Using transcription factor footprint and chromatin accessibility, we systemically cataloged regulatory elements (REs) denoted as SHS-I/II, KHS-I/II, +6.5kb^Il13, 5HS-I(a, b, c, d, e), 5HS-II and 5HS-III(a, b, c) across the extended Il4-Il13-Il5 locus in mice. Physical proximities among REs were coordinately remodeled in three-dimensional space after cell activation, leading to divergent compartmentalization of Il4, Il13 and Il5 with varied combinations of REs. Deletions of REs revealed no single RE solely accounted for selective regulation of a given cytokine in vivo. Instead, individual RE differentially contribute to proper genomic positioning of REs and target genes. RE deletions resulted in context-dependent dysregulation of cytokine expression and immune response in tissue. Thus, signal-dependent remodeling of three-dimensional configuration underlies divergent cytokine outputs from the type 2 loci.

2 型细胞因子白细胞介素 （IL）-4、IL-13 和 IL-5 存在于多基因簇中。先天性 （ILC2） 和适应性辅助性 T 细胞 2 （T_H2） 淋巴细胞都分泌具有不同产生光谱的 2 型细胞因子。利用转录因子足迹和染色质可及性，我们对小鼠扩展的 Il4-Il13-Il5 基因座上表示为 SHS-I/II、KHS-I/II、+6.5kb^Il13、5HS-I（a、b、c、d、e）、5HS-II 和 5HS-III（a、b、c）的调节元件 （REs） 进行了系统分类。细胞活化后，RE 之间的物理接近在三维空间中协调重塑，导致 Il4、Il13 和 Il5 与 RE 的不同组合出现不同的区室化。RE 的缺失表明，没有单个 RE 仅解释体内给定细胞因子的选择性调节。相反，单个 RE 差异有助于 RE 和靶基因的正确基因组定位。RE 缺失导致组织中细胞因子表达和免疫反应的环境依赖性失调。因此，三维构型的信号依赖性重塑是 2 型基因座不同细胞因子输出的基础。