Human CCR6+ Th cells show both an extended stable gradient of Th17 activity and imprinted plasticity

Th17 cells have been investigated in mice primarily for their contributions to autoimmune diseases. However, the pathways of differentiation of Th17 and related (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 RORgt. 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 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.

辅助性T细胞17（Th17 cells）在小鼠中的研究主要围绕其在自身免疫疾病中的功能展开。然而，人类Th17及相关17型细胞的分化通路、17型记忆细胞群的构成尚未被充分阐明；此类认知是实现体内调控这类细胞的关键基础。本研究通过利用表面趋化因子受体6（CCR6）的表达水平差异，发现人类17型记忆细胞（包括单个T细胞克隆型）可形成一条延伸的17型特性连续谱系，随着视黄酸相关孤儿受体γt（RORγt）表达水平提升，细胞的17型特性可被逐步驱动强化。该谱系包含留存于记忆库中的细胞，其潜能反映了多谱系相较于单谱系的早期优先激活特征。在稳态条件下，CCR6阳性细胞的表型与表观基因组在多轮细胞分裂中保持稳定。不过，在极化与非极化培养条件下激活后，这类细胞可获得额外的功能属性，这分别揭示了环境诱导与细胞印记两种机制：二者在整个谱系中发挥差异化的调控作用，共同造就了17型细胞所特有的异常可塑性。