Delivery of progenitors to the thymus limits T-lineage reconstitution after bone marrow transplantation

Abstract

T-cell production depends on the recruitment of hematopoietic progenitors into the thymus. T cells are among the last of the hematopoietic lineages to recover after bone marrow transplantation (BMT), but the reasons for this delay are not well understood. Under normal physiologic conditions, thymic settling is selective and either CCR7 or CCR9 is required for progenitor access into the thymus. The mechanisms of early thymic reconstitution after BMT, however, are unknown. Here we report that thymic settling is briefly CCR7/CCR9-independent after BMT but continues to rely on the selectin ligand PSGL-1. The CCR7/CCR9 independence is transient, and by 3 weeks after BMT these receptors are again strictly required. Despite the normalization of thymic settling signals, the rare bone marrow progenitors that can efficiently repopulate the thymus are poorly reconstituted for at least 4 weeks after BMT. Consistent with reduced progenitor input to the thymus, intrathymic progenitor niches remain unsaturated for at least 10 weeks after BMT. Finally, we show that thymic recovery is limited by the number of progenitors entering the thymus after BMT. Hence, T-lineage reconstitution after BMT is limited by progenitor supply to the thymus. (Blood. 2011;118(7): 1962-1970) IntroductionT cells provide critical immune protection from a range of pathogens. The T-lineage is the slowest to recover after irradiation and bone marrow transplantation (BMT), a delay that impairs immunologic protection of the host. 1 Peripheral T-cell reconstitution after BMT occurs through 2 mechanisms: one thymusindependent and one thymus-dependent. First, radioresistant host T cells and donor T cells provided in the graft homeostatically proliferate in the lymphopenic postirradiation environment. 2,3 Although this population expansion can partially correct numerical T-cell defects, the resulting cells are functionally compromised. 4,5 The functional recovery of the T-lineage relies on the second mechanism: the de novo generation of naive T cells in the thymus. 6,7 The generation of thymus-derived naive T cells can take years and is particularly slow in adults. 1,2,8 The reasons for this delay are not fully understood but have been suggested to involve impaired intrathymic development because of thymic stromal damage from conditioning regimens, age-related thymic involution, and graft-versus-host disease (GVHD). [9][10][11] The thymus does not contain self-renewing progenitors and therefore requires the importation of circulating bone marrow (BM)-derived progenitors to sustain thymopoiesis. [12][13][14] Thymic settling, however, is suggested to be a rare event, and the identity of thymic settling progenitors remains unclear. [15][16][17] All progenitors descend from hematopoietic stem cells (HSCs), which are phenotypically negative for lineage markers (Lin) and are additionally Kit ϩ Sca1 ϩ Flt3 Ϫ . Directly downstream of HSCs are nonrenewing multipotent progenitors (MPPs; Lin Ϫ Kit ϩ Sca1 ϩ Flt3 low ), 18 which in turn give rise to lymphoid-primed multipot...

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

“…Other findings also strongly support continued translational studies for the development of IT -based HSC transplantation strategies including: (a) a significantly more rapid kinetics of T-cell reconstitution following IT as compared to IV administration of HSC and (b) long-term thymopoiesis by IT-injected precursors in nonconditioned recipients, even across histocompatibility barriers (Fig. 2) [23,41,57,[60][61][62]. It will therefore be important to determine the clinical settings in which an IT transplantation approach, potentially enhancing HSC differentiation to a T lineage fate, will improve short-as well as long-term patient outcome.…”

Intrathymic progenitor cell transplantation across histocompatibility barriers results in the persistence of early thymic progenitors and T-cell differentiation

“…Indeed, it has recently been shown that thymus permeability is increased by more than fivefold after myeloablative conditioning. 30 In our experiments, BM engraftment of conditioned mice treated by intravenous transplantation reached levels of more than 90%, but BM donor cells in intrathymic-transplanted mice were also elevated, accounting for at least 30% of lineage-negative BM progenitors ( Figure 5). The high BM engraftment of progenitors was associated with the maturation of donor B lymphocytes, although ZAP-70-deficient host precursors are completely capable of B-cell differentiation (Figure 2).…”

“…However, it is striking that immediately after conditioning by irradiation, the requirement for CCR7/CCR9 is abolished. 30 Thus, it is possible that in our conditioned ZAP-70-deficient mice, the absence of donor progenitor cell expansion and/or long-term persistence after intrathymic transplantation is because of an early competition from incoming endogenous progenitors as well as the presence of a less favorable thymic niche.…”

CD4+ T Cell–Depleted Lymphocyte Infusion Impairs Neither the Recovery of Recipient Thymus nor the Development of Transplanted Thymus

“…Because the recipient thymus is impaired by the conditioning regimen (especially irradiation), the thymic reconstitution takes ∼10 wk; T cells are the last hematopoietic lineage cells to recover after BMT in mice and humans (32). To improve this situation, we combined TT with BMT to provide a new environment for T cell induction and differentiation.…”