EOMES-dependent epigenetic reprogramming during CD8 T cell development leads to acquisition of memory traits (ChIP-Seq). EOMES-dependent epigenetic reprogramming during CD8 T cell development leads to acquisition of memory traits (ChIP-Seq)

Memory CD8 T cells have a unique ability to provide lifelong immunity against pathogens. Although memory features generally arise after a challenge with foreign antigen, naïve CD8 single positive (SP) thymocytes may already acquire phenotypic and functional characteristics of memory cells in response to cytokines such as interleukin-4. This process is associated with the induction of the T-box transcription factor Eomesodermin (EOMES). However, the underlying molecular mechanisms remain ill-defined. Using epigenomic profiling, we show that these “innate memory” CD8SP cells acquire only a portion of the active enhancer repertoire of conventional memory cells. This reprograming was secondary to EOMES recruitment, mostly to RUNX3-bound enhancers. Furthermore, we identified direct interaction between EOMES and BRG1 and showed that in vivo acquisition of EOMES-dependent program by CD8SP thymocytes was dependent on this chromatin remodeling factor. In conclusion, our results support a strong epigenetic basis for EOMES-driven establishment of CD8 T cell unconventional memory program. Overall design: CD8SP thymocytes: Innate Memory, Naïve, WT, and Eomes-TG

记忆性CD8 T细胞拥有独特的能力，可介导针对病原体的终生免疫防御。尽管记忆性特征通常在遭遇外来抗原后才会形成，但初始CD8单阳性（single positive, SP）胸腺细胞在应答白细胞介素-4等细胞因子时，即可获得记忆细胞的表型与功能特征。该过程与T-box转录因子Eomesodermin（EOMES）的诱导表达相关。然而，其背后的分子机制仍未明确。通过表观基因组分析，我们发现这类“固有记忆”CD8SP细胞仅获得了常规记忆细胞活性增强子组库的一部分。该重编程过程依赖于EOMES的招募，且招募位点主要集中在结合了RUNX3的增强子区域。此外，我们证实了EOMES与BRG1之间存在直接相互作用，并证明CD8SP胸腺细胞在体内获取EOMES依赖性转录程序的过程，依赖于该染色质重塑因子。综上，我们的研究结果证实，EOMES介导的CD8 T细胞非经典记忆程序建立过程具有坚实的表观遗传基础。实验设计概况：CD8SP胸腺细胞分为固有记忆型、初始型、野生型（wild type, WT）以及Eomes转基因型（Eomes-TG）四组。