Biomedical subjects

Aleksandar Dakic

Publications and source records attributed to Aleksandar Dakic.

7 recordsLinked to original sources

PubMed2006

Inactivation of PU.1 in adult mice leads to the development of myeloid leukemia.

Genetically primed adult C57BL mice were deleted of exon 5 of the gene encoding the transcription factor PU.1 by IFN activation of Cre recombinase. After a 13-week delay, conditionally deleted (PU.1(-/-)) mice began dying of myeloid leukemia, and 95% of the mice surviving from early postinduction death developed transplantable myeloid leukemia whose cells were deleted of PU.1 and uniformly Gr-1 positive. The leukemic cells formed autonomous colonies in semisolid culture with varying clonal efficiency, but colony formation was enhanced by IL-3 and sometimes by granulocyte-macrophage colony-stimulating factor. Nine of 13 tumors analyzed had developed a capacity for autocrine IL-3 or granulocyte-macrophage colony-stimulating factor production, and there was evidence of rearrangement of the IL-3 gene. Acquisition of autocrine growth-factor production and autonomous growth appeared to be major events in the transformation of conditionally deleted PU.1(-/-) cells to fully developed myeloid leukemic populations.

Animals↗

PubMed2005

The development of functional B lymphocytes in conditional PU.1 knock-out mice.

An abundance of research has entrenched the view that the Ets domain containing transcription factor PU.1 is fundamental to the development and function of B lymphocytes. In this study, we have made use of a conditional PU.1 allele to test this notion. Complete deletion of PU.1 resulted in the loss of B cells and all other lineage-positive cells in the fetal liver and death between E18.5 and birth; however, specific deletion of PU.1 in the B lineage had no effect on B-cell development. Furthermore, deletion of PU.1 in B cells did not compromise their ability to establish and maintain an immune response. An increased level of apoptosis was observed in vitro upon B-cell receptor (BCR) cross-linking; however, this was partially rescued by interleukin-4 (IL-4). These findings suggest that PU.1 is not essential for the development of functional B lymphocytes beyond the pre-B stage.

Animals↗

PubMed2005

Cutting edge: generation of splenic CD8+ and CD8- dendritic cell equivalents in Fms-like tyrosine kinase 3 ligand bone marrow cultures.

We demonstrate that functional and phenotypic equivalents of mouse splenic CD8(+) and CD8(-) conventional dendritic cell (cDC) subsets can be generated in vitro when bone marrow is cultured with fms-like tyrosine kinase 3 (flt3) ligand. In addition to CD45RA(high) plasmacytoid DC, two distinct CD24(high) and CD11b(high) cDC subsets were present, and these subsets showed equivalent properties to splenic CD8(+) and CD8(-) cDC, respectively, in the following: 1) surface expression of CD11b, CD24, and signal regulatory protein-alpha; 2) developmental dependence on, and mRNA expression of, IFN regulatory factor-8; 3) mRNA expression of TLRs and chemokine receptors; 4) production of IL-12 p40/70, IFN-alpha, MIP-1alpha, and RANTES in response to TLR ligands; 5) expression of cystatin C; and 6) cross-presentation of exogenous Ag to CD8 T cells. Furthermore, despite lacking surface CD8 expression, the CD24(high) subset contained CD8 mRNA and up-regulated surface expression when transferred into mice. This culture system allows access to bona fide counterparts of the splenic DC subsets.

Animals↗

PubMed2005

PU.1 regulates the commitment of adult hematopoietic progenitors and restricts granulopoiesis.

Although the transcription factor PU.1 is essential for fetal lymphomyelopoiesis, we unexpectedly found that elimination of the gene in adult mice allowed disturbed hematopoiesis, dominated by granulocyte production. Impaired production of lymphocytes was evident in PU.1-deficient bone marrow (BM), but myelocytes and clonogenic granulocytic progenitors that are responsive to granulocyte colony-stimulating factor or interleukin-3 increased dramatically. No identifiable common lymphoid or myeloid progenitor populations were discernable by flow cytometry; however, clonogenic assays suggested an overall increased frequency of blast colony-forming cells and BM chimeras revealed existence of long-term self-renewing PU.1-deficient cells that required PU.1 for lymphoid, but not granulocyte, generation. PU.1 deletion in granulocyte-macrophage progenitors, but not in common myeloid progenitors, resulted in excess granulocyte production; this suggested specific roles of PU.1 at different stages of myeloid development. These findings emphasize the distinct nature of adult hematopoiesis and reveal that PU.1 regulates the specification of the multipotent lymphoid and myeloid compartments and restrains, rather than promotes, granulopoiesis.

Animals↗

PubMed2004

Development of the dendritic cell system during mouse ontogeny.

Based on the view that the efficacy of the immune system is associated with the maturation state of the immune cells, including dendritic cells (DC), we investigated the development and functional potential of conventional DC and plasmacytoid pre-DC (p-preDC) in spleen, thymus, and lymph nodes during mouse development. Both CD11c+ DC and CD45RA+ p-preDC were detected in small numbers in the thymus as early as embryonic day 17. The ratio of DC to thymocytes reached adult levels by 1 wk, although the normal CD8alpha+ phenotype was not acquired until later. Significant, but low, numbers of DC and p-preDC were present in the spleen of day 1 newborn mice. The full complement of DC and p-preDC was not acquired until 5 wk of age. The composition of DC populations in the spleen of young mice differed significantly from that found in adult mice, with a much higher percentage (50-60% compared with 20-25%) of the CD4-CD8alpha+ DC population and a much lower percentage (10-20% compared with 50-60%) of the CD4+CD8alpha- DC population. Although the p-preDC of young mice showed a capacity to produce IFN-alpha comparable with that of adult mice, the conventional DC of young mice were less efficient than those of their adult counterparts in IL-12p70 and IFN-gamma production and in Ag presentation. These results suggest that the neonatal DC system is not fully developed, and innate immunity is the dominant form of response. The complete DC system required for adaptive immunity in the mouse is not fully developed until 5 wk of age.

Aging↗

PubMed2004

Development of dendritic cell system.

The dendritic cell system contains conventional dendritic cells (DCs) and plasmacytoid pre-dendritic cells (pDCs). Both DCs and pDCs are bone marrow derived cells. Although the common functions of DCs are antigen-processing and T-lymphocyte activation, they differ in surface markers, migratory patterns, and cytokine output. These differences can determine the fate of the T cells they activate. Several subsets of mature DCs have been described in both mouse and human and the developmental processes of these specialized DC subsets have been studied extensively. The original concept that all DCs were of myeloid origin was questioned by several recent studies, which demonstrated that in addition to the DCs derived from myeloid precursors, some DCs could also be efficiently generated from lymphoid-restricted precursors. Moreover, it has been shown recently that both conventional DCs and pDCs can be generated by the Flt3 expressing hemopoietic progenitors regardless of their myeloid- or lymphoid-origin. These findings suggest an early developmental flexibility of precursors for DCs and pDCs. This review summarizes some recent observations on the development of DC system in both human and mouse.

Animals↗

PubMed2003

Hemopoietic precursors and development of dendritic cell populations.

The antigen presenting dendritic cells (DCs) are bone marrow (BM) derived cells. Despite their common functions of antigen-processing and T-lymphocyte activation, DCs are diverse in surface markers, migratory patterns and cytokine output. These differences can determine the fate of the T cells they activate. Several subsets of mature DCs have been described in both mouse and human, but tracing the origin of these specialised DC subsets has not been a trivial task. The original concept that all DCs were of myeloid origin was questioned by several recent studies, which demonstrated that in addition to the DCs derived from conventional myeloid precursors, some DCs could also be efficiently generated from lymphoid-restricted precursors. Moreover, it has been shown that both myeloid-restricted and lymphoid-restricted precursors were able to generate DC subsets with similar surface phenotype. These observations demonstrate the existence of both myeloid- and lymphoid-derived DC lineages and suggest an early developmental flexibility of DC precursors. The downstream points where the DC sub-lineages branch off from the conventional myeloid and lymphoid precursors, and the cytokines and environmental factors required for inducing their specialised functions are yet to be determined.

Animals↗