![]() ![]() The developmental potential of immature human thymocyte subsets has mainly been studied in vitro but does not necessarily correlate with actual in vivo differentiation. Furthermore, it is unclear in human which other hematopoietic lineages develop intrathymically. Also CD34 +CD38 - thymocytes have been proposed to comprise the most immature precursor subset ( Dik et al., 2005 Weerkamp et al., 2006). Multiple thymus seeding populations have been reported based on differential CD7 expression and these have led to conflicting reports on whether CD34 +CD7 - ( Hao et al., 2008 Six et al., 2007) or CD34 +CD7 int ( Haddad et al., 2006) precursors reflect the thymus-seeding progenitors. In each case, the uncommitted fraction of human thymocytes has an unknown heterogeneity in which a small fraction should represent the BM-derived immigrating T cell precursors. While CD1a upregulation within these CD34 + thymocytes has been used to mark T-lineage commitment, recent work has proposed that the commitment process is already initiated within the most immature CD34 +CD1a - thymocytes and marked by the loss of CD44 expression within that subset ( Canté-Barrett et al., 2017). Immature human thymocytes are characterized by the human stem/progenitor cell marker CD34. Also functional perturbation experiments have suggested that the molecular mechanisms driving early T cell development in human might differ compared to in mouse ( Ha et al., 2017 Taghon et al., 2009 Van de Walle et al., 2009, 2016). ![]() This is clearly exemplified by the differences in cell surface markers that are used to phenotype the most immature T cell precursors and this has obscured a clear comparison of these initial stages of T cell development across species. Experimental mouse models have been extensively used to study the early stages of T cell development, but extrapolation of these insights to human biology has proven to be difficult due to species specific differences. Notch1 activation in these T cell progenitors is one of the main drivers of these early events and is initiated through interaction with Notch1 ligands such as DLL4 expressed by the thymic epithelial cells. The thymic microenvironment gradually converts these immigrating and still multipotent progenitor cells to become T-lineage committed, and also induces extensive proliferation to increase the pool of T cell precursors. Maintenance of physiological thymopoiesis requires the continuous colonization of a small amount of bone marrow (BM) derived T cell precursors whose identity is still unclear in human. T lymphocytes require the specific microenvironment of the thymus for their development. ![]() To facilitate and optimize their generation and to enhance T cell recovery in patients, insights into the molecular processes that drive early T cell development after birth are of critical importance. In addition to their protective role against pathogens, T cells are increasingly exploited for immunotherapeutic purposes, particularly through the generation of CAR T-cells. T cell deficiencies result in life-threatening conditions, such as perturbed and delayed T cell reconstitution following chemo- and radiotherapy. T cells are central and essential mediators of the adaptive immune system. Thus, our work resolves the heterogeneity of thymus seeding precursors in human and reveals the molecular mechanisms that drive their in vivo cell fate. Trough trajectory inference, we delineate the transcriptional dynamics underlying early human T-lineage development from which we predict transcription factor modules that drive stage-specific steps of human T cell development. Besides T cell precursors, we discover branches of intrathymic developing dendritic cells with predominantly plasmacytoid DCs. Integration of bone marrow and peripheral blood precursors datasets identifies several putative thymus seeding precursors that display heterogeneity for currently used surface markers as revealed by CITEseq. Here, we employ single-cell RNA sequencing on approximately 70.000 CD34 + thymocytes to unravel the heterogeneity of the human immature postnatal thymocytes. In human, the nature of these thymus immigrants has remained unclear. During postnatal life, thymopoiesis depends on the continuous colonization of the thymus by bone marrow derived hematopoietic progenitors that migrate through the bloodstream.
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