Division of Neonatology and the Children's Health and Discovery Initiative, Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.
HIV Frontiers, Global Health Accelerator, Bill & Melinda Gates Foundation, Seattle, Washington, USA.
Immunol Rev. 2023 May;315(1):126-153. doi: 10.1111/imr.13195. Epub 2023 Mar 24.
The switch from primitive to definitive hematopoiesis occurs early in development through the emergence of a wave of definitive hematopoietic stem cells from intraembryonic sites, supplanting the original primitive population of extraembryonically derived stem cells. When it became clear that unique features of the fetal immune system could not be reproduced by adult stem cells, it was hypothesized that a lineage of definitive fetal hematopoietic stem cells predominates antenatally, ultimately giving way to an emerging wave of adult stem cells and resulting in a "layered" fetal immune system consisting of overlapping lineages. It is now clear, however, that the transition from human fetal-to-adult T cell identity and function does not occur due to a binary switch between distinct fetal and adult lineages. Rather, recent evidence from single cell analysis suggests that during the latter half of fetal development a gradual, progressive transition occurs at the level of hematopoietic stem-progenitor cells (HSPCs) which is reflected in their T cell progeny. At a transcriptional level, clusters of genes are up- and down-regulated with sequenced timing, suggesting that the transition is under the control of master regulatory factors, including epigenetic modifiers. The net effect is still one of "molecular layering," that is, the continuous layering of iterative generations of HSPCs and T cells that arise through progressive changes in gene expression. This review will focus on recent discoveries that elucidate mechanisms of fetal T cell function and the transition from fetal to adult identity. The epigenetic landscape of fetal T cells facilitates their ability to fulfill the dominant fetal mandate of generating tolerance against self, maternal, and environmental antigens by supporting their predisposition to differentiate into CD25 FoxP3 regulatory T cells (T ). We will explore how the coordinated development of two complementary populations of fetal T cells-conventional T cells dominated by T and tissue-associated memory effector cells with innate-like inflammatory potential-is crucial not only for maintaining intrauterine immune quiescence but also for facilitating an immune response that is appropriately tuned for the bombardment of antigen stimulation that happens at birth.
从原始到确定性造血的转变发生在早期发育过程中，通过来自胚胎内部位的确定性造血干细胞的出现，取代了胚胎外来源的原始干细胞的原始群体。当人们清楚地认识到胎儿免疫系统的独特特征不能被成人干细胞复制时，人们假设在产前存在一个确定性胎儿造血干细胞谱系占主导地位，最终让位于新兴的成人干细胞波，从而形成一个“分层”的胎儿免疫系统，由重叠的谱系组成。然而，现在很清楚，人类胎儿到成人 T 细胞身份和功能的转变不是由于独特的胎儿和成人谱系之间的二进制开关发生的。相反，最近来自单细胞分析的证据表明，在胎儿发育的后半期，造血干细胞-祖细胞（HSPC）水平会发生逐渐、渐进的转变，这反映在其 T 细胞后代中。在转录水平上，基因簇随着时间的推移被上调和下调，表明这种转变受主调控因子的控制，包括表观遗传修饰因子。其净效应仍然是“分子分层”，即通过基因表达的逐步变化，HSPC 和 T 细胞的迭代产生的连续分层。这篇综述将重点介绍最近的发现，这些发现阐明了胎儿 T 细胞功能和从胎儿到成人身份转变的机制。胎儿 T 细胞的表观遗传景观促进了它们发挥作用的能力，即通过支持其向 CD25 FoxP3 调节性 T 细胞（Treg）分化的倾向，产生对自身、母体和环境抗原的耐受性。我们将探讨如何协调两种互补的胎儿 T 细胞群体——以 T 细胞为主导的常规 T 细胞和具有先天样炎症潜能的组织相关记忆效应细胞——的发展，不仅对维持子宫内免疫静止至关重要，而且对促进出生时发生的抗原刺激的免疫反应也至关重要。
