Human CCR6+ Th cells show both an extended stable gradient of Th17 activity and imprinted plasticity [BeadChipHumanWG-6]. Human CCR6+ Th cells show both an extended stable gradient of Th17 activity and imprinted plasticity [BeadChipHumanWG-6]

Th17 cells have been investigated in mice primarily for their contributions to autoimmune diseases. However, the pathways of differentiation of Th17 and related Th cells (type 17 cells) and the structure of the type 17 memory population in humans are not well understood; such understanding is critical for manipulating these cells in vivo. By exploiting differences in levels of surface CCR6, we found that human type 17 memory cells, including individual T cell clonotypes, form an elongated continuum of type 17 character along which cells can be driven by increasing RORt. This continuum includes cells preserved within the memory pool with potentials that reflect the early preferential activation of multiple over single lineages. The CCR6+ cells’ phenotypes and epigenomes are stable across cell divisions under homeostatic-like conditions. Nonetheless, activation in polarizing and non-polarizing conditions can yield additional functionalities, revealing, respectively, both environmentally induced and imprinted mechanisms that contribute differentially across the continuum to yield the unusual plasticity ascribed to type 17 cells. Overall design: Illumina BeadChip RNA expression assay of 9 human donors, CD4+CD45RO- and CD4+CD45RO+ T-cells sorted into CCR6neg, CCR6low, CCR6int and CCR6high subsets, with or without PMA stimulation

辅助性T细胞17（Th17 cells）在小鼠中的研究主要聚焦于其在自身免疫疾病中的功能贡献。然而，目前人类体内辅助性T细胞17（Th17 cells）及相关17型辅助性T细胞（type 17 cells）的分化通路，以及17型记忆细胞群（type 17 memory population）的结构特征尚未得到充分阐明；此类认知对于在体内调控这类细胞至关重要。本研究利用表面趋化因子受体CCR6（CCR6）的表达水平差异，发现人类17型记忆细胞（含单个T细胞克隆型）可构成一条延伸的17型特性连续谱系，且可通过上调维A酸相关孤儿受体γt（RORγt）的表达驱动细胞沿该谱系分布。该谱系涵盖了留存于记忆细胞库中的细胞，其潜能反映了多谱系相较于单谱系的早期优先激活特性。在类稳态培养条件下，CCR6阳性细胞的表型与表观基因组在细胞分裂过程中保持稳定。尽管如此，在极化与非极化培养条件下的细胞激活可赋予其额外功能，分别揭示了环境诱导与印记调控两类机制——这类机制在整个谱系中发挥差异化作用，最终赋予17型细胞特有的可塑性。实验整体设计：对9名人类供体的CD4+CD45RO阴性及CD4+CD45RO阳性T细胞进行分选，将其分为CCR6阴性、低表达、中等表达及高表达亚群，并设置是否经佛波醇肉豆蔻酸乙酸酯（PMA）刺激组，随后采用伊卢米纳（Illumina）BeadChip芯片开展RNA表达分析。