Tcf1 is known to function as a transcriptional activator of Wnt-induced proliferation during T cell development in the thymus. Evidence for an additional contrasting role for Tcf1 as a T-cell specific tumor suppressor gene is now presented.
The Wnt signaling pathway is essential in the development and homeostasis of blood and immune cells, but its exact role is still controversial and is the subject of intense research. The malignant counterpart of normal hematopoietic cells, leukemic (stem) cells, have hijacked the Wnt pathway for their self-renewal and proliferation. Here we review the multiple ways dysregulated Wnt signaling can contribute to leukemogenesis, both cell autonomously as well as by changes in the microenvironment.
Hepatic NK cells constitute $40% of hepatic lymphocytes and are phenotypically and functionally distinct from blood NK cells. Whether hepatic NK cells derive from precursors in the BM or develop locally from hepatic progenitors is still unknown. Here, we identify all five known sequential stages of NK-cell development in the adult human liver and demonstrate that CD34 1 hepatic progenitors can generate functional NK cells. While early NK-cell precursors (NKPs) were similar in liver and blood, hepatic stage 3 NKPs displayed immunophenotypical differences, suggesting the onset of a liver-specific NK-cell development. Hepatic stage 3 NKPs were RORC neg and did not produce IL-17 or IL-22, excluding them from the lymphoid tissue-inducer (LTi) subset. In vitro culture of hepatic NKPs gave rise to functional NK cells exhibiting strong cytotoxicity against K562 targets. To determine whether hepatic NKPs are stably residing in the liver, we analyzed donor and recipient-derived cells in transplanted livers. Shortly after liver transplantation all donor NKPs in liver grafts were replaced by recipient-derived ones, indicating that hepatic NKPs are recruited from the bloodstream. Together, our results show that NKPs are continuously recruited from peripheral blood into the liver and can potentially differentiate into liverspecific NK cells.
The mechanisms that regulate proliferation, fate decisions and differentiation of hematopoietic stem cells (HSC) and thymic stem cells are highly complex. Several signaling pathways including Wnt signaling have important roles during these processes. Both canonical and non-canonical Wnt signaling are important in normal and malignant hematopoiesis and lymphoid development, yet their precise roles are controversial. In a side-by-side comparison, we investigated the roles of the canonical and non-canonical Wnt pathway in hematopoiesis and thymopoiesis. As complete loss-of-function models for non-canonical Wnt signaling are not yet available and highly complex for canonical Wnt signaling, we decided to use a gain-of-function approach. To this end, Wnt3a and Wn5a, two well-known prototypical canonical and non-canonical Wnt ligands were produced in hematopoiesis supporting stromal assays. High levels of Wnt3a signaling blocked T-cell development at early stages, whereas intermediate levels accelerated T-cell development. In contrast, Wnt5a signaling prompted apoptosis in developing thymocytes, without affecting differentiation at a particular stage. To explore the role of Wnt3a and Wnt5a in vivo, we transduced HSCs isolated from fetal liver, transduced with Wnt3a and Wnt5a vectors, and performed reconstitution assays in irradiated C57Bl/6 mice. Wnt3a overexpression led to increased lymphopoiesis, whereas Wnt5a augments myelopoiesis in the bone marrow (BM) and spleen. Thus, the canonical and non-canonical Wnt signaling have discrete roles in hematopoiesis and thymopoiesis, and understanding their right dose of action is crucial for prospective translational applications.
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