PDF(Pubmed)
Abstract：
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 CD27, CD28, and ICOS 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 CD8+CCR7loCD45RAhi 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 CD8+CCR7loCD45RAhi sorted cells, we found a decreased proportion of IL7R+ Tcm/em-like and MAIT cells in individuals with high levels of CMV antibodies (CMVhi). These results shed new light on the molecular and cellular heterogeneity of CD8+ Temra cells and their relationship to aging and CMV infection.
摘要：
随着人类年龄的增长,由于终生暴露于抗原，它们的记忆T细胞区室扩大。这种扩增的特征是终末分化的CD8+T细胞（Temra），具有NK细胞样表型并与慢性炎症相关。Temra细胞主要由散发性巨细胞病毒（CMV）的再激活驱动，然而，他们的表观基因组模式和细胞异质性仍未得到充分研究。为了解决这个差距，我们将它们的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，将它们与其他CD8+亚群和CMV反应进行比较。我们证实Temra细胞表现出与细胞毒性相关的基因的高表达和共刺激和趋化因子基因的低表达。数据显示，CMV反应性CD8T细胞（Tcmv）主要来自Temra和记忆细胞（Tcm/em）的混合群体，并共享其转录组学谱。使用ATAC-SEQ分析，我们确定了CD8+Temra和Tcm/em细胞之间的1449个差异接近染色质区域，其中只有127个位点在Temra细胞中获得染色质可及性。我们进一步鉴定了51个基因位点，包括共刺激CD27、CD28和ICOS基因，其染色质可及性与其基因表达相关。差异染色质区Tcm/em细胞富含结合多种转录激活因子的基序，例如Jun/Fos，NFkappaB,STAT,而Temra细胞的开放区域主要含有T-box转录因子的结合位点。我们对CD8CCR7loCD45RAhi分选的Temra群体的单细胞分析显示，老年个体中Temra和NKT样细胞和CMC1Temra群体的几个亚群已向降低的细胞毒性转移。在CD8+CCR7loCD45RAhi分选的细胞中，我们发现，在CMV抗体（CMVhi）水平高的个体中，IL7RTcm/em样和MAIT细胞的比例降低。这些结果为CD8Temra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思路。
