Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
Leiden Computational Biology Center, Leiden University Medical Center, Leiden, the Netherlands.
Nat Immunol. 2019 Mar;20(3):301-312. doi: 10.1038/s41590-018-0294-9. Epub 2019 Jan 21.
The fetus is thought to be protected from exposure to foreign antigens, yet CD45RO T cells reside in the fetal intestine. Here we combined functional assays with mass cytometry, single-cell RNA sequencing and high-throughput T cell antigen receptor (TCR) sequencing to characterize the CD4 T cell compartment in the human fetal intestine. We identified 22 CD4 T cell clusters, including naive-like, regulatory-like and memory-like subpopulations, which were confirmed and further characterized at the transcriptional level. Memory-like CD4 T cells had high expression of Ki-67, indicative of cell division, and CD5, a surrogate marker of TCR avidity, and produced the cytokines IFN-γ and IL-2. Pathway analysis revealed a differentiation trajectory associated with cellular activation and proinflammatory effector functions, and TCR repertoire analysis indicated clonal expansions, distinct repertoire characteristics and interconnections between subpopulations of memory-like CD4 T cells. Imaging mass cytometry indicated that memory-like CD4 T cells colocalized with antigen-presenting cells. Collectively, these results provide evidence for the generation of memory-like CD4 T cells in the human fetal intestine that is consistent with exposure to foreign antigens.
人们认为胎儿受到保护，不会接触到外来抗原，但 CD45RO T 细胞存在于胎儿肠道中。在这里，我们结合功能测定、质谱流式细胞术、单细胞 RNA 测序和高通量 T 细胞抗原受体（TCR）测序，对人胎儿肠道中的 CD4 T 细胞区室进行了表征。我们鉴定出 22 个 CD4 T 细胞簇，包括类似初始、调节性和记忆样亚群，这些亚群在转录水平得到了确认和进一步的特征分析。记忆样 CD4 T 细胞高表达 Ki-67，这是细胞分裂的标志，还高表达 CD5，这是 TCR 亲和力的替代标志物，并且产生 IFN-γ 和 IL-2 等细胞因子。通路分析显示出与细胞激活和促炎效应功能相关的分化轨迹，TCR 库分析表明存在克隆扩增、独特的库特征以及记忆样 CD4 T 细胞亚群之间的相互联系。成像质谱流式细胞术表明，记忆样 CD4 T 细胞与抗原呈递细胞共定位。总之，这些结果为人类胎儿肠道中记忆样 CD4 T 细胞的产生提供了证据，这与接触外来抗原是一致的。
