![]() ![]() 16 One such strategy is the adoptive transfer of T-cell precursors to rapidly restore the T-cell compartment and T-cell–mediated immunity after HSCT. 14, 15 Thus, the development of strategies to enhance T-lymphopoiesis remains an important task. 13 The increased susceptibility to opportunistic infections is specifically caused by poor T-cell recovery and the absence of de novo T-cell generation from HSC-derived progenitors found in the BM. HSC transplantation (HSCT) is a mainstay for the treatment of hematologic malignancies, however, an extended delay in immune-reconstitution after transplantation leads to cases of morbidity and mortality and remains a clinical challenge. 7, 8 Thus, candidate populations with T-cell potential have been reported from UCB and BM. 10 Nevertheless, the presence of a Lin −CD34 +CD38 +CD10 +CD45RA +CD7 −/low common lymphoid progenitor population in human BM with T-cell potential has been described, 11 as well as an umbilical cord blood-derived CD34 +CD38 −CD7 + common lymphoid progenitor population 12 and a CD34 +CD45RA hiCD7 + population from UCB and fetal BM possessing T-cell potential. ![]() ![]() However, the exact nature of the thymus-seeding cell arriving from the BM remains unknown. A separate study by Hao et al 9 has demonstrated that a rare population of Lin −CD34 +CD7 − thymocytes is detectable and thus may correspond to an earlier intrathymic progenitor. CD7 is one of the earliest markers to appear during human T-cell ontogeny and analysis of human fetal and postnatal organs by Haddad et al 7, 8 showed that an early T-lineage progenitor in humans corresponds to a CD34 +CD45RA +CD7 + population. Although HSCs do not directly seed the thymus, 6 CD34 + cells are present in human thymus. 4, 5 Human HSCs are found within the lineage negative (Lin −) CD34 +CD38 − compartment. Under steady state conditions, the thymus does not contain a self-renewing cell, and the production of T-cells throughout life must be maintained by the continued recruitment of blood-borne progenitors arriving from the BM. Our findings provide further support for the use of Notch-expanded progenitors in cell-based therapies to aid in the recovery of T-cells in patients undergoing HSCT. Furthermore, we uncovered a potential mechanism by which receptor activator of nuclear factor κb (RANK) ligand–expressing proT2-cells induce changes in both the function and architecture of the thymus microenvironment, which favors the recruitment of bone marrow-derived lymphoid progenitors. Based on this, when proT2-cells were coinjected with HSCs, a significantly improved and accelerated HSC-derived T-lymphopoiesis was observed. Although the 2 subsets tested (proT1, CD34 +CD7 +CD5 − proT2, CD34 +CD7 +CD5 +) showed thymus engrafting function, proT2-cells exhibited superior engrafting capacity. A competitive transfer approach was used to define the optimal proT subset capable of reconstituting immunodeficient mice. We examined whether co-transplantation of in vitro–derived human proT-cells with hematopoietic stem cells (HSCs) was able to facilitate HSC-derived T-lymphopoiesis posttransplant. Here, we addressed whether in vitro–derived human progenitor T (proT)-cells could not only represent a source of thymus-seeding progenitors, but also able to influence the recovery of the thymic microenvironment. Underlying causes are a severely dysfunctional thymus and an impaired production of thymus-seeding progenitors in the host. Hematopoietic stem cell transplantation (HSCT) is followed by a period of immune deficiency due to a paucity in T-cell reconstitution. ![]()
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