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David Allman

Publications and source records attributed to David Allman.

31 records · Page 2Linked to original sources
PubMed2004

Alternative routes to maturity: branch points and pathways for generating follicular and marginal zone B cells.

Positive and negative selection of developing B cells is critical for generating a functional non-pathogenic B-cell repertoire. Newly formed B cells in the bone marrow or peripheral lymphoid system can be eliminated by one of several negative selection mechanisms or recruited through a poorly understood positive selection mechanism. In this review, we focus on the growing literature on the relevance of immature (transitional) peripheral B cells to the area of B-cell positive selection, with an emphasis on the notion that transitional B cells can be subdivided into several functionally distinct subpopulations. In this discussion, we consider the nature of these transitional B-cell subsets and their relevance to selection events that influence whether developing B cells eventually give rise to follicular versus marginal zone B cells. In addition, we attempt to initiate a resolution of current controversies surrounding transitional B-cell subsets and offer an alternative model of peripheral B-cell maturation and the follicular versus marginal zone decision.

Animals↗
PubMed2003

The decline in B lymphopoiesis in aged mice reflects loss of very early B-lineage precursors.

The primary age-related loss in B cell progenitors is thought to be at the pro- to pre-B cell transition. However, we show that the frequencies and absolute numbers of all progenitor populations for the B cell lineage, including B-lineage-committed pro-B cells and multipotent B-lymphoid progenitors, decline in aged C57BL/6 mice. Moreover, when derived from aged mice, lymphoid progenitors within every population examined exhibited suboptimal IL-7 responsiveness, demonstrating that age-associated suboptimal IL-7R signaling is a general property of all early B-lineage precursors. Collectively, these data indicate that aging results in a previously unappreciated decline in the earliest stages of B cell development.

Aging↗
PubMed2003

Thymopoiesis independent of common lymphoid progenitors.

Early T lineage progenitors (ETPs) in the thymus are thought to develop from common lymphoid progenitors (CLPs) in the bone marrow (BM). We compared thymic ETPs to BM CLPs in mice and found that they differed in several respects. Thymic ETPs were not interleukin 7 (IL-7)-responsive and generated B lineage progeny with delayed kinetics, whereas BM CLPs were IL-7-responsive and rapidly generated B cells. ETPs sustained production of T lineage progeny for longer periods of time than BM CLPs. Analysis of Ikaros-deficient mice that exhibit ongoing thymopoiesis without B lymphopoeisis revealed near-normal frequencies of thymic ETPs, yet undetectable numbers of BM CLPs. We conclude that ETPs can develop via a CLP-independent pathway.

Animals↗
PubMed2003

Common lymphoid progenitors, early B-lineage precursors, and IL-7: characterizing the trophic and instructive signals underlying early B cell development.

Precursors for B lymphocytes develop from semirestricted lymphoid progenitors in the bone marrow. Here we review current knowledge on the cellular stages underlying early B cell development from multipotent progenitor cells, and discuss the factors implicated in the regulation of this process. In particular, we will focus on the role of cytokine receptor signaling in early lymphocyte ontogeny and lymphoid lineage commitment, with an emphasis on the role of interleukin- 7 (IL-7) in early lymphocyte development within the bone marrow microenvironment. We will also discuss recent evidence that lymphocytes and subsets of dendritic cells develop from a common pathway, speculating that IL-7 may regulate cell fate decisions in multipotent B/dendritic cell precursors by driving these cells to differentiate into B-lineage-committed cells.

Animals↗
PubMed2002

Oscillation between B-lymphoid and myeloid lineages in Myc-induced hematopoietic tumors following spontaneous silencing/reactivation of the EBF/Pax5 pathway.

B lymphomagenesis is an uncontrolled expansion of immature precursors that fail to complete their differentiation program. This failure could be at least partly explained by inappropriate expression of several oncogenic transcription factors, such as Pax5 and Myc. Both Pax5 and c-Myc are implicated in the pathogenesis of non-Hodgkin lymphomas. To address their role in lymphomagenesis, we analyzed B-cell lymphomas derived from p53-null bone marrow progenitors infected in vivo by a Myc-encoding retrovirus. All Myc-induced lymphomas invariably maintained expression of Pax5, which is thought to be incompatible with terminal differentiation. However, upon culturing in vitro, several cell lines spontaneously down-regulated Pax5 and its target genes CD19, N-Myc, and MB1. Unexpectedly, other B-cell markers (eg, CD45R) were also down-regulated, and markers of myeloid lineage (CD11b and F4/80 antigen) were acquired instead. Moreover, cells assumed the morphology reminiscent of myeloid cells. A pool of F4/80-positive cells as well as several single-cell clones were obtained and reinjected into syngeneic mice. Remarkably, pooled cells rapidly re-expressed Pax5 and formed tumors of relatively mature lymphoid phenotype, with surface immunoglobulins being abundantly expressed. Approximately half of tumorigenic single-cell clones also abandoned myeloid differentiation and gave rise to B lymphomas. However, when secondary lymphoma cells were returned to in vitro conditions, they once again switched to myeloid differentiation. This process could be curbed via enforced expression of retrovirally encoded Pax5. Our data demonstrate that some Myc target cells are bipotent B-lymphoid/myeloid progenitors with the astonishing capacity to undergo successive rounds of lineage switching.

Animals↗
PubMed2002

The earliest step in B lineage differentiation from common lymphoid progenitors is critically dependent upon interleukin 7.

Little is known about the signals that promote early B lineage differentiation from common lymphoid progenitors (CLPs). Using a stromal-free culture system, we show that interleukin (IL)-7 is sufficient to promote the in vitro differentiation of CLPs into B220(+) CD19(+) B lineage progenitors. Consistent with current models of early B cell development, surface expression of B220 was initiated before CD19 and was accompanied by the loss of T lineage potential. To address whether IL-7 receptor (R) activity is essential for early B lineage development in vivo, we examined the frequencies of CLPs and downstream pre-pro- and pro-B cells in adult mice lacking either the alpha chain or the common gamma chain (gamma(c)) of the IL-7R. The data indicate that although gamma(c)(-/-) mice have normal frequencies of CLPs, both gamma(c)(-/-) and IL-7R(alpha)(-/-) mice lack detectable numbers of all downstream early B lineage precursors, including pre-pro-B cells. These findings challenge previous notions regarding the point in B cell development affected by the loss of IL-7R signaling and suggest that IL-7 plays a key and requisite role during the earliest phases of B cell development.

Animals↗
PubMed2002

Differential requirement for LAT and SLP-76 in GPVI versus T cell receptor signaling.

Mice deficient in the adaptor Src homology 2 domain-containing leukocyte phosphoprotein of 76 kD (SLP-76) exhibit a bleeding disorder and lack T cells. Linker for activation of T cells (LAT)-deficient mice exhibit a similar T cell phenotype, but show no signs of hemorrhage. Both SLP-76 and LAT are important for optimal platelet activation downstream of the collagen receptor, GPVI. In addition, SLP-76 is involved in signaling mediated by integrin alphaIIbbeta3. Because SLP-76 and LAT function coordinately in T cell signal transduction, yet their roles appear to differ in hemostasis, we investigated in detail the functional consequences of SLP-76 and LAT deficiencies in platelets. Previously we have shown that LAT(-/-) platelets exhibit defective responses to the GPVI-specific agonist, collagen-related peptide (CRP). Consistent with this, we find that surface expression of P-selectin in response to high concentrations of GPVI ligands is reduced in both LAT- and SLP-76-deficient platelets. However, platelets from LAT(-/-) mice, but not SLP-76(-/-) mice, aggregate normally in response to high concentrations of collagen and convulxin. Additionally, unlike SLP-76, LAT is not tyrosine phosphorylated after fibrinogen binding to integrin alphaIIbbeta3, and collagen-stimulated platelets deficient in LAT spread normally on fibrinogen-coated surfaces. Together, these findings indicate that while LAT and SLP-76 are equally required for signaling via the T cell antigen receptor (TCR) and pre-TCR, platelet activation downstream of GPVI and alphaIIbbeta3 shows a much greater dependency on SLP-76 than LAT.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Generation of a syngeneic mouse model to study the effects of vascular endothelial growth factor in ovarian carcinoma.

Vascular endothelial growth factor (VEGF) performs multifaceted functions in the tumor microenvironment promoting angiogenesis, suppressing anti-tumor immune response, and possibly exerting autocrine functions on tumor cells. However, appropriate syngeneic animal models for in vivo studies are lacking. Using retroviral transfection and fluorescence-activated cell sorting, we generated a C57BL6 murine ovarian carcinoma cell line that stably overexpresses the murine VEGF164 isoform and the enhanced green fluorescent protein. VEGF164 overexpression dramatically accelerated tumor growth and ascites formation, significantly enhanced tumor angiogenesis, and substantially promoted the survival of tumor cells in vivo. In vitro, VEGF164 overexpression significantly enhanced cell survival after growth factor withdrawal and conferred resistance to apoptosis induced by cis-platin through an autocrine mechanism. VEGF/green fluorescent protein-expressing tumors were not recognized by the adaptive immune system. After vaccination, a specific anti-tumor T-cell response was detected, but tumor growth was not inhibited. This engineered murine carcinoma model should prove useful in the investigation of the role of VEGF in modulating the tumor microenvironment and affecting the complex interactions among angiogenesis mechanisms, anti-tumor immune mechanisms, and tumor cell behavior at the natural state or during therapy in ovarian carcinoma.

Animals↗
PubMed2002

An invitation to T and more: notch signaling in lymphopoiesis.

Cell fate decisions in metazoans are regulated by Notch signals. During lymphoid development, Notch influences a series of cell fate decisions involving multipotent progenitors. This review focuses on current views and lingering uncertainties about Notch function in lymphoid cells.

Animals↗
PubMed2002

Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1.

Notch1 signaling drives T cell development at the expense of B cell development from a common precursor, an effect that is dependent on a C-terminal Notch1 transcriptional activation domain. The function of Deltex1, initially identified as a positive modulator of Notch function in a genetic screen in Drosophila, is poorly understood. We now demonstrate that, in contrast to Notch1, enforced expression of Deltex1 in hematopoietic progenitors results in B cell development at the expense of T cell development in fetal thymic organ culture and in vivo. Consistent with these effects, Deltex1 antagonizes Notch1 signaling in transcriptional reporter assays by inhibiting coactivator recruitment. These data suggest that a balance of inductive Notch1 signals and inhibitory signals mediated through Deltex1 and other modulators regulate T-B lineage commitment.

3T3 Cells↗
PubMed2002

Notch signaling in hematopoiesis and early lymphocyte development.

Notch signals regulate multiple cell fate decisions during metazoan development. During hematopoiesis, Notch affects both hematopoietic stem cells and committed progenitors. In hematopoietic stem cells, Notch signaling has the propensity to expand the stem cells, promote their self-renewal, and influence their survival. In committed progenitors, Notch signaling plays a key role in determining lymphoid cell fates. This review focuses on recent developments to understand the role of Notch signaling in early events in hematopoiesis.

Animals↗
PubMed2002

Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor, CD28 and 4-1BB.

The ex vivo priming and expansion of human cytotoxic T lymphocytes (CTLs) has potential for use in immunotherapy applications for cancer and infectious diseases. To overcome the difficulty in obtaining sufficient numbers of CTLs, we have developed artificial antigen-presenting cells (aAPCs) expressing ligands for the T-cell receptor (TCR) and the CD28 and 4-1BB co-stimulatory surface molecules. These aAPCs reproducibly activate and rapidly expand polyclonal or antigen-specific CD8(+) T cells. The starting repertoire of CD8+ T cells was preserved during culture. Furthermore, apoptosis of cultured CD8(+) T cells was diminished by this approach. This approach may have important therapeutic implications for adoptive immunotherapy.

Antigen-Presenting Cells↗