Biology subjects

Martins, V. C.

Publications and source records attributed to Martins, V. C..

4 recordsLinked to original sources

bioRxiv2025

Limited bone marrow chimerism impairs thymic cell competition and causes leukemia

Cell competition in the thymus is a critical tumor suppressor process that prevents leukemia. We show that suboptimal bone marrow correction of {gamma}c-deficient mice disrupts this process, inducing thymus autonomy and promoting T cell acute lymphoblastic leukemia (T-ALL). {gamma}c-deficiency causes severe combined immunodeficiency in mice and humans and is treated by hematopoietic stem and progenitor cell (HSPC) transplantation. However, inefficient correction led to intermittent thymic activity, consistent with sporadic thymus seeding. This was accompanied by altered thymocyte composition and the emergence of an aberrant TCR{beta}{square}CD4{square}CD8{square} population that preceded overt leukemia. Leukemia incidence and latency were exacerbated when HSPCs were pre-cultured under conditions mimicking gene-editing protocols, whereas delaying thymopoietic support in the host mitigated disease. Critically, the extent of bone marrow reconstitution determined the ability to suppress thymus autonomy and leukemia development. Together, these findings demonstrate that inadequate bone marrow correction directly compromises thymic cell competition, creating a permissive niche for malignant transformation. Our work highlights thymus autonomy as a risk in immunodeficiency treatment and underscores the need to ensure robust hematopoietic reconstitution to prevent leukemogenesis.

immunology↗

bioRxiv2021

Interleukin 7 receptor drives Early T lineage Progenitor expansion

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.

immunology↗

bioRxiv2020

Self-renewal capacity of double negative 3 (DN3) early thymocytes preserves thymus autonomous function but compromises the β-selection checkpoint

T lymphocyte differentiation in the thymus relies on high cellular turnover, and cell competition enforces thymocyte replenishment. 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, were necessary for autonomous thymopoiesis, and included DNA-label-retaining 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 {beta}-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.

immunology↗

bioRxiv2019

Cell competition regulates the kinetics of thymopoiesis and thymus cellularity

Cell competition in the thymus is a homeostatic process that drives turnover. If the process is impaired, thymopoiesis can be autonomously maintained for several weeks, but this causes 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 occurs within the double negative 2 (DN2) and 3 early (DN3e) thymocytes and inhibits thymus autonomy. Furthermore, the expansion of 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 dynamically integrates cell autonomous and non-cell autonomous aspects that fine-tune normal thymus function.

immunology↗