Dynamics of Thymus-Colonizing Cells during Human Development

Abstract

Here, we identify fetal bone marrow (BM)-derived CD34hiCD45RAhiCD7+ hematopoietic progenitors as thymus-colonizing cells. This population, virtually absent from the fetal liver (FL), emerges in the BM by development weeks 8-9, where it accumulates throughout the second trimester, to finally decline around birth. Based on phenotypic, molecular, and functional criteria, we demonstrate that CD34hiCD45RAhiCD7+ cells represent the direct precursors of the most immature CD34hiCD1a- fetal thymocytes that follow a similar dynamics pattern during fetal and early postnatal development. Histological analysis of fetal thymuses further reveals that early immigrants predominantly localize in the perivascular areas of the cortex, where they form a lymphostromal complex with thymic epithelial cells (TECs) driving their rapid specification toward the T lineage. Finally, using an ex vivo xenogeneic thymus-colonization assay, we show that BM-derived CD34hiCD45RAhiCD7+ progenitors are selectively recruited into the thymus parenchyma in the absence of exogenous cytokines, where they adopt a definitive T cell fate.

T-, B- and NK-lymphoid, but not myeloid cells arise from human CD34+CD38−CD7+ common lymphoid progenitors expressing lymphoid-specific genes

“…In addition to their T-cell differentiation potential, fetal CD34 hi CD1a À thymocytes possess strong NKcell potential, as well as B-and dendritic cell potential, but lack granulocyte/macrophage potential. 32 Weerkamp et al recently showed that the adult CD34 þ CD1a À thymocyte subset has differentiation potential not only for B, NK and dendritic cells, but also for myeloid and erythroid lineages, 33 leading to the hypothesis that the adult human thymus is seeded by a multipotent stem cell-like progenitor instead of a CLP. Still, the multilineage differentiation capacity of both fetal and adult early thymocytes remains to be shown at the single cell level, thus the possibility exists that, analogously to the corresponding murine DN1 thymocyte stage (CD44 þ CD25 À ), 34 the human CD34 þ CD1a À thymic subset is heterogeneous and contains multiple progenitors with different differentiation potential.…”

Identification of TMEM131L as a Novel Regulator of Thymocyte Proliferation in Humans

“…Umbilical cord blood and postnatal thymuses, collected according to institutional guidelines, were processed as described (1,20). Thymocyte populations were purified based on positive or negative selection with an autoMACS system (Miltenyi Biotec) or a FACSAria II cell sorter (BD Biosciences).…”

“…F ollowing extravasation from the blood, early thymus immigrants establish lymphostromal synapses with cortical thymic epithelial cells, which triggers proliferation and drives their specification along the T cell lineage through the simultaneous activation of the IL-7R, c-Kit, sonic hedgehog, Wnt/ LEF/T cell factor (TCF), and Notch signaling pathways (1)(2)(3). Most current evidence suggests that activation of the Frizzled/ LRP6 receptor complex by its cognate ligands (Wnt1-4) regulates survival and proliferation of early thymus immigrants, whereas Notch1 ligation by Delta-like 4 also drives commitment toward the T lineage (4).…”

Hématopoïèse humaine : des cellules CD34 aux lymphocytes T

“…Moins nombreuses et souvent contradictoires sont les informations concernant les molécules impliquées dans ce processus chez l'homme. Chez ce dernier, les thymocytes foetaux immatures semblent exprimer préférentiellement les récepteurs CXCR4 et, plus faiblement, CCR9 [15], et il semble que l'acquisition du récepteur CXCR4 sur les cellules CD34 + de la moelle osseuse s'accompagne de la perte du potentiel myéloïde et d'une restriction du développement aux lymphocytes T et B [16]. Ces données, concordantes avec celles obtenues par Haddad et ses collaborateurs sur les thymocytes foetaux, sont en contradiction avec celles publiées par Hernandez-Lopez et ses collaborateurs [17], qui montrent que les progéniteurs thymiques CD1a négatifs n'expriment pas ce récepteur.…”

“…En revanche, un certain consensus existe sur le fait que, in vivo, le CLP ne colonise pas de façon majeure le thymus, son potentiel T s'exprimant surtout in vitro. Chez l'homme, le thymus pourrait également être colonisé par des progéniteurs multipotents [18] ou par un progéniteur lymphoïde commun capable de donner naissance exclusivement à des cellules B, NK et dendritiques, comme cela a été montré pendant la période foetale [15] et, d'une façon moins complète, dans le sang de cordon [7,8] (Figure 2). Il n'existe cependant aucune information sur l'identité et la caractérisation des progéniteurs qui colonisent le thymus après la naissance et pendant la vie adulte, et leur présence simultanée dans la circulation et dans le thymus n'a jamais été démontrée.…”