Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
Qiagen Aarhus A/S, Aarhus, Denmark.
Front Immunol. 2024 Feb 2;15:1285798. doi: 10.3389/fimmu.2024.1285798. eCollection 2024.
As humans age, their memory T cell compartment expands due to the lifelong exposure to antigens. This expansion is characterized by terminally differentiated CD8 T cells (Temra), which possess NK cell-like phenotype and are associated with chronic inflammatory conditions. Temra cells are predominantly driven by the sporadic reactivation of cytomegalovirus (CMV), yet their epigenomic patterns and cellular heterogeneity remain understudied. To address this gap, we correlated their gene expression profiles with chromatin openness and conducted single-cell transcriptome analysis, comparing them to other CD8 subsets and CMV-responses. We confirmed that Temra cells exhibit high expression of genes associated with cytotoxicity and lower expression of costimulatory and chemokine genes. The data revealed that CMV-responsive CD8 T cells (Tcmv) were predominantly derived from a mixed population of Temra and memory cells (Tcm/em) and shared their transcriptomic profiles. Using ATAC-seq analysis, we identified 1449 differentially accessible chromatin regions between CD8 Temra and Tcm/em cells, of which only 127 sites gained chromatin accessibility in Temra cells. We further identified 51 gene loci, including costimulatory , , and genes, whose chromatin accessibility correlated with their gene expression. The differential chromatin regions Tcm/em cells were enriched in motifs that bind multiple transcriptional activators, such as Jun/Fos, NFkappaB, and STAT, whereas the open regions in Temra cells mainly contained binding sites of T-box transcription factors. Our single-cell analysis of CD8CCR7CD45RA sorted Temra population showed several subsets of Temra and NKT-like cells and CMC1 Temra populations in older individuals that were shifted towards decreased cytotoxicity. Among CD8CCR7CD45RA sorted cells, we found a decreased proportion of IL7R Tcm/em-like and MAIT cells in individuals with high levels of CMV antibodies (CMV). These results shed new light on the molecular and cellular heterogeneity of CD8 Temra cells and their relationship to aging and CMV infection.
随着人类年龄的增长，由于终生暴露于抗原，其记忆 T 细胞区室会扩张。这种扩张的特点是终末分化的 CD8 T 细胞（Temra），其具有 NK 样表型，与慢性炎症状态有关。Temra 细胞主要由巨细胞病毒（CMV）的偶发性再激活驱动，但它们的表观基因组模式和细胞异质性仍未得到充分研究。为了解决这一差距，我们将其基因表达谱与染色质开放性相关联，并进行了单细胞转录组分析，将其与其他 CD8 亚群和 CMV 反应进行了比较。我们证实 Temra 细胞表现出与细胞毒性相关的基因的高表达，以及共刺激和趋化因子基因的低表达。数据显示，CMV 反应性 CD8 T 细胞（Tcmv）主要来自 Temra 和记忆细胞（Tcm/em）的混合群体，并且具有相似的转录组谱。使用 ATAC-seq 分析，我们在 CD8 Temra 和 Tcm/em 细胞之间鉴定了 1449 个差异可及染色质区域，其中 Temra 细胞中只有 127 个位点获得染色质可及性。我们进一步鉴定了 51 个基因座，包括共刺激基因、和基因，其染色质可及性与其基因表达相关。Tcm/em 细胞差异染色质区域富含结合多个转录激活子的基序，如 Jun/Fos、NFkappaB 和 STAT，而 Temra 细胞中的开放区域主要包含 T 框转录因子的结合位点。我们对 CD8CCR7CD45RA 分选的 Temra 群体的单细胞分析显示，在老年人中存在几个 Temra 和 NKT 样细胞和 CMC1 Temra 亚群，其细胞毒性呈下降趋势。在 CD8CCR7CD45RA 分选的细胞中，我们发现高水平 CMV 抗体（CMV）个体中 IL7R Tcm/em 样和 MAIT 细胞的比例降低。这些结果为 CD8 Temra 细胞的分子和细胞异质性及其与衰老和 CMV 感染的关系提供了新的认识。
