Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunol. 2011 Sep 15;187(6):3111-20. doi: 10.4049/jimmunol.1101283. Epub 2011 Aug 17.
Each of the three Th2 cytokine genes, IL-4, IL-5, and IL-13, has different functions. We hypothesized that Th2 heterogeneity could yield Th2 subpopulations with different cytokine expression and effector functions. Using multiple approaches, we demonstrate that human Th2 cells are composed of two major subpopulations: a minority IL-5(+) (IL-5(+), IL-4(+), IL-13(+)) and majority IL-5(-) Th2 (IL-5(-), IL-4(+), IL-13(+)) population. IL-5(+) Th2 cells comprised only 20% of all Th2 cells. Serial rounds of in vitro differentiation initially yielded IL-5(-) Th2, but required multiple rounds of differentiation to generate IL-5(+) Th2 cells. IL-5(+) Th2 cells expressed less CD27 and greater programmed cell death-1 than IL-5(-) Th2 cells, consistent with their being more highly differentiated, Ag-exposed memory cells. IL-5(+) Th2 cells expressed greater IL-4, IL-13, and GATA-3 relative to IL-5(-) Th2 cells. GATA-3 and H3K4me(3) binding to the IL5 promoter (IL5p) was greater in IL-5(+) relative to IL-5(-) Th2 cells, whereas there was no difference in their binding to the IL4p and IL13p. Conversely, H3K27me(3) binding to the IL5p was greater in IL-5(-) Th2 cells. These findings demonstrate Th2 lineage heterogeneity, in which the IL5 gene is regulated in a hierarchical manner relative to other Th2 genes. IL-5(+) Th2 cells are phenotypically distinct and have epigenetic changes consistent with greater IL5p accessibility. Recurrent antigenic exposure preferentially drives the differentiation of IL-5(+) Th2 cells. These results demonstrate that IL-5(+) and IL-5(-) Th2 cells, respectively, represent more and less highly differentiated Th2 cell subpopulations. Such Th2 subpopulations may differentially contribute to Th2-driven pathology.
三种 Th2 细胞因子基因（IL-4、IL-5 和 IL-13）各有不同的功能。我们假设 Th2 异质性可能产生具有不同细胞因子表达和效应功能的 Th2 亚群。我们采用多种方法证明，人类 Th2 细胞由两个主要亚群组成：少数 IL-5(+)（IL-5(+)、IL-4(+)、IL-13(+)）和多数 IL-5(-) Th2（IL-5(-)、IL-4(+)、IL-13(+)）群体。IL-5(+) Th2 细胞仅占所有 Th2 细胞的 20%。体外分化的连续循环最初产生 IL-5(-) Th2，但需要多轮分化才能产生 IL-5(+) Th2 细胞。IL-5(+) Th2 细胞表达的 CD27 较少，程序性细胞死亡 1 较高，表明它们是分化程度更高、抗原暴露的记忆细胞。与 IL-5(-) Th2 细胞相比，IL-5(+) Th2 细胞表达更高水平的 IL-4、IL-13 和 GATA-3。与 IL-5(-) Th2 细胞相比，GATA-3 和 H3K4me(3) 与 IL5 启动子（IL5p）的结合在 IL-5(+) Th2 细胞中更强，而与 IL4p 和 IL13p 的结合则没有差异。相反，IL-5(-) Th2 细胞中 IL5p 的 H3K27me(3) 结合更强。这些发现表明 Th2 谱系存在异质性，其中 IL5 基因相对于其他 Th2 基因呈分级调控。IL-5(+) Th2 细胞表型独特，具有与更高的 IL5p 可及性一致的表观遗传变化。反复的抗原暴露优先驱动 IL-5(+) Th2 细胞的分化。这些结果表明，IL-5(+) 和 IL-5(-) Th2 细胞分别代表了更高度和低度分化的 Th2 细胞亚群。这种 Th2 亚群可能会对 Th2 驱动的病理学产生不同的影响。
