Thymus autonomy is the capacity of the thymus to maintain T lymphocyte development and export independently of bone marrow contribution. Prolonging thymus autonomy was shown to be permissive to the development of T cell acute lymphoblastic leukemia (T-ALL), similar to the human disease. In this study, performing thymus transplantation experiments in mice, we report that thymus autonomy can occur in several experimental conditions, and all are permissive to TALL. We show that wild type thymi maintain their function of T lymphocyte production upon transplantation into recipients with several genotypes (and corresponding phenotypic differences), i.e., Rag2 2/2 g c 2/2 , g c 2/2 , Rag2 2/2 IL-7ra 2/2 , and IL-7ra 2/2. We found that the cellularity of the thymus grafts is influenced exclusively by the genotype of the host, i.e., IL-7ra 2/2 versus g c 2/2. Nonetheless, the difference in cellularity detected in thymus autonomy bore no impact on onset, incidence, immunophenotype, or pathologic condition of TALL. In all tested conditions, TALL reached an incidence of 80%, demonstrating that thymus autonomy bears a high risk of leukemia. We also analyzed the microbiota composition of the recipients and their genetic background, but none of the differences found influenced the development of TALL. Taken together, our data support that IL-7 drives cellular turnover non-cell autonomously, which is required for prevention of TALL. We found no influence for TALL in the specific combination of the genotypic mutations tested (including the developmental block caused by Rag deficiency), in microbiota composition, or minor differences in the genetic background of the strains.
Highlights d Cell competition in the thymus is mediated by DN2 and DN3e and promotes turnover d DN2b are sensitive to a negative feedback loop imposed by more mature thymocytes d The cellularity of DN2/DN3 is determined by availability and response to IL-7 d The DN2/DN3 cellularity defines cell competition and the kinetics of thymopoiesis
Cell competition in the thymus promotes turnover and functions as a tumor suppressor by inhibiting leukemia. Using thymus transplantation experiments, we have shown that the presence of T lymphocyte precursors, recently seeding the thymus, promotes the clearance of precursors with a longer time of thymus residency. If cell competition is impaired and no cells seed the thymus, the organ is capable of sustaining T lymphocyte production, a state termed thymus autonomy. However, we observed consistently that prolonged autonomy is permissive to the emergence of T cell acute lymphoblastic leukemia (T-ALL). This resembled the onset of T-ALL in patients treated by gene therapy for X-linked severe combined immunodeficiency (SCID-X1). Following treatment, thymus activity was established, with T lymphocyte production, although no bone marrow contribution was detected. However, some patients developed T-ALL. The favored explanation for malignant transformation was considered to be genotoxicity due to integration of the retroviral vector next to oncogenes, thereby activating them ectopically. Although plausible, we consider an alternative, mutually nonexclusive explanation: that any condition enabling prolonged thymus autonomy will promote leukemogenesis. In support of this view, two independent studies have recently shown that the efficacy of reconstitution of the bone marrow in the context of SCID-X1 dramatically influences the outcome of treatment, and that lymphoid malignancies emerge following transplantation of a small number of healthy progenitors. Here, we discuss the most recent data in light of our own studies in thymopoiesis and the conditions that trigger malignant transformation of thymocytes in various experimental and clinical settings.
Self-renewal of double-negative 3 early thymocytes enables thymus autonomy but compromises the b-selection checkpoint Graphical abstract Highlights d Thymus autonomy depends on DN3e thymocytes that secure T cell differentiation d DN3e in autonomy self-renew, retain DNA label, and have enhanced proliferation d Thymus autonomy preserves the hallmarks of thymopoiesis at the single-cell level d Aberrant cells with active notch that bypassed b-selection emerge in autonomy
Cell competition in the thymus is a homeostatic process that drives cellular turnover. If the process is impaired, thymopoiesis can be autonomously maintained for several weeks, but such condition is permissive to leukemia. We aimed to understand the impact of cell competition on thymopoiesis, identify the cells involved and determine how the process is regulated. Using thymus transplantation experiments we found that cell competition is mediated by double negative 2b (DN2b) and 3 (DN3) thymocytes and inhibits thymus autonomy. The expansion of the DN2b is regulated by a negative feedback loop imposed by double positive thymocytes and determines the kinetics of thymopoiesis. This feedback loop impacts on cell cycle duration of DN2b, in a response controlled by interleukin 7 availability. Altogether, we show that thymocytes do not merely follow a pre-determined path if provided with the correct signals. Instead, thymopoiesis results from the dynamic integration of cell autonomous and non-cell autonomous aspects that fine-tune normal thymus function.
IL-7 and IL-7R are essential for T lymphocyte differentiation by driving proliferation and survival of specific developmental stages. Although early T lineage progenitors (ETPs), the most immature thymocyte population known, have a history of IL-7R expression, it is unclear whether IL-7R is required at this stage. In this study, we show that mice lacking IL-7 or IL-7R have a marked loss of ETPs that results mostly from a cell-autonomous defect in proliferation and survival, although no changes were detected in Bcl2 protein levels. Furthermore, a fraction of ETPs responded to IL-7 stimulation ex vivo by phosphorylating Stat5, and IL-7R was enriched in the most immature Flt3+Ccr9+ ETPs. Consistently, IL-7 promoted the expansion of Flt3+ but not Flt3− ETPs on OP9-DLL4 cocultures, without affecting differentiation at either stage. Taken together, our data show that IL-7/IL-7R is necessary following thymus seeding by promoting proliferation and survival of the most immature thymocytes.
T lymphocyte differentiation in the thymus relies on high cellular turnover, which is enforced by cell competition. If deprived of competent progenitors, the thymus can maintain thymopoiesis autonomously for several weeks but this bears a high risk of leukemia. Here we show that double negative 3 early (DN3e) thymocytes can acquire stem cell like properties, which enables them to maintain thymopoiesis. Specifically, DN3e proved to be long-lived, they proliferated and differentiated in vivo, they were necessary for autonomous thymopoiesis, and included DNA-labelretaining cells. Single cell RNAseq revealed a transcriptional program of thymopoiesis similar in autonomy and the controls. Nevertheless, a new population was identified in thymus autonomy that was enriched for an aberrant Notch target gene signature and bypassed the b-selection checkpoint.In sum, DN3e have the potential to self-renew and differentiate in vivo if cell competition is compromised but this enables the accumulation of atypical cells, probably leading to leukemia.
Interleukin 7 (IL-7) and IL-7 receptor (IL-7r) are essential for T lymphocyte differentiation, by driving proliferation and survival of specific developmental stages. While early T lineage progenitors (ETP), the most immature thymocyte population known, have a history of IL-7r expression, it is unclear whether IL-7r is required at this stage. Here, we show that mice lacking IL-7 or IL-7r have a marked loss of ETPs that results mostly from a cell-autonomous defect in proliferation and survival, although no changes were detected in Bcl2 protein levels. Further, a fraction of ETPs responded to IL-7 stimulation ex vivo by phosphorylating Stat5, and IL-7r was enriched in the most immature Flt3+Ccr9+ ETPs. Consistently, IL-7 promoted the expansion of Flt3+ but not Flt3-ETPs on OP9-DLL4 cocultures, without affecting differentiation at either stage. Taken together, our data show that IL-7/IL-7r is necessary following thymus seeding, by promoting proliferation and survival of the most immature thymocytes.SummaryPaiva et al. show that IL-7/IL-7r signaling upon thymus seeding is essential for proliferation and survival of the most immature early T lineage progenitors (ETP), thereby determining the physiological ETP cellularity.
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