![]() ![]() Subsequently, these αβ-lineage T cells undergo positive and negative selection in the thymus in order to establish major histocompatibility complex (MHC)-restricted pathogen recognition and central tolerance, respectively. Upon replacement of the pTα by an in-frame rearranged TCRα chain, a functional TCRαβ is expressed on the cell surface together with the CD3 co-receptor. These DP T cells then enter a quiescent state to permit V(D)J recombination of the TCRA locus. Upon pre-TCR signaling, developing thymocytes receive proliferation and survival signals and up-regulate CD8β to differentiate into CD4 +CD8β + double positive (DP) T cells. During αβ-lineage development, an in-frame rearranged TCRβ chain associates with the invariant pre-T cell receptor α chain (pTα) in order to generate the pre-TCR that induces β-selection, an event that mainly occurs at the CD4 + immature single positive (ISP) stage. The outcome of these TCR rearrangement events is the main driver of the developmental bifurcation of the αβ- and γδ-lineages which mainly occurs at the ISP stage, and this allows both lineages to mature into distinct T cell subsets that have unique functions in the periphery. During the induction of T cell development, rearrangements of the TCRD, TCRG and TCRB loci are initiated in a process called V(D)J recombination which leads to the generation of functional T cell receptors (TCRs). These pro-T cells will then fully lose the capacity to differentiate into non-T cells by committing to the T cell lineage which is generally characterized by the up-regulation of CD1a, although more recently the loss of CD44 was found to more accurately define human T cell commitment. Subsequently, upon induction of IL-7 signaling and continuous Notch stimulation, these ETPs develop into progenitor T cells (pro-T cells) and display a decreased potential to develop into other hematopoietic lineages. Upon intra-thymic Notch signaling, predominantly initiated by the NOTCH1–DLL4 axis, the expression of CD7 is highly up-regulated in the TSPs as they differentiate into early T cell progenitors (ETPs). Because of its distinct anatomical site compared with where HSCs reside, immature precursors need to egress from the BM in order to colonize the thymus, starting from week 8 of gestation. T cell development occurs in the thymus, a small organ located in the thoracic cavity that instructs HSC-derived thymus seeding precursors (TSPs) to differentiate along the T cell lineage in response to the micro-environmental stimuli that it provides ( Figure 1). T-lineage potential has been regarded as a hallmark of definitive HSCs. ![]() ![]() Understanding the nature of HSCs has important implications for their in vitro generation and use in the clinic. Upon birth, these HSCs will cease to proliferate and acquire a quiescent state in order to maintain lifelong postnatal hematopoiesis. Finally, HSCs will colonize the developing bone marrow (BM) which is the most dominant site of hematopoiesis starting from 20 weeks of gestation. These HSCs will subsequently migrate to the fetal liver (FL) where they expand and further support hematopoiesis during fetal life. The definitive wave of embryonic hematopoiesis is characterized by the generation of the first self-renewing HSCs that have multilineage hematopoietic potential. Following primitive hematopoiesis, the definitive program is initiated, at day 32 of gestation, within the dorsal aorta of the aorta-gonad-mesonephros (AGM) region which originates from the embryonic mesoderm. The primitive program of hematopoiesis occurs after 3 weeks of gestation in the blood islands of the extra-embryonic yolk sac (YS) and generates a transient wave of mainly primitive erythroblasts, megakaryocytes and macrophages. In the human embryo, hematopoiesis is characterized by a primitive and a definitive wave which are spatiotemporally separated and have different characteristics. These multipotent HSCs originate or reside in specific niches that are located at different sites throughout life. ![]() Hematopoiesis is a strictly regulated process in which hematopoietic stem cells (HSCs) gradually lose multipotency in order to generate the full repertoire of blood cells that comprise the hematopoietic system. Access content during the Covid-19 pandemic. ![]()
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