Defining the molecular mechanisms underlying immunological memory in T cells (expression)

Immunological memory is a defining feature of animal development, allowing rapid responses to repeat infections, yet the very basis of T cell-dependent memory remains poorly understood. Here we demonstrate that the critical steps in the acquisition of T cell memory occur not after completion of T cell differentiation but during the initial activation phase of naïve T cells, when extensive chromatin remodelling reprograms immune response genes towards a stably maintained primed state. During this process, inducible factors including AP-1 create hundreds of DNase I hypersensitive sites (DHSs), allowing the recruitment of ETS1 and RUNX1 to sites that were previously inaccessible. Significantly, these DHSs remain temporally and mitotically stable long after cessation of AP-1 activation, and function to maintain regions of active chromatin in the vicinity of genes that regulate immune responses. This priming enables increased accessibility and the accelerated induction of other inducible regulatory elements in previously activated T cells. Examination of gene expression patterns in naïve, blast, memory T-cells with or without PMA activation via microarray study.

免疫记忆（Immunological memory）是动物发育的标志性特征，可介导机体对重复感染产生快速应答，但T细胞依赖性记忆的核心机制仍有待深入阐明。本研究证实，T细胞记忆获得的关键步骤并非发生于T细胞分化完成之后，而是在初始T细胞（naïve T cells）的初始活化阶段：此时大规模的染色质重塑（chromatin remodelling）将免疫应答相关基因重编程为稳定维持的预致敏状态。在此过程中，包括AP-1在内的诱导型转录因子会形成数百个DNase I超敏位点（DNase I hypersensitive sites, DHSs），使得ETS1与RUNX1能够结合至此前无法接触的染色质区域。值得注意的是，即便在AP-1活化停止后很长一段时间内，这些DHSs仍能在时序维度和有丝分裂过程中保持稳定，其功能是维持免疫应答调控基因附近区域的染色质活性状态。这种预致敏状态可提升染色质可及性，并加速此前活化的T细胞中其他诱导型调控元件的诱导进程。本研究通过基因芯片（microarray）技术，检测了初始T细胞、淋巴母细胞及记忆T细胞在经PMA活化与未经活化状态下的基因表达谱。