scholarly journals Activated Notch2 Potentiates CD8 Lineage Maturation and Promotes the Selective Development of B1 B Cells

2003 ◽  
Vol 23 (23) ◽  
pp. 8637-8650 ◽  
Author(s):  
Colleen M. Witt ◽  
Vincent Hurez ◽  
C. Scott Swindle ◽  
Yoshio Hamada ◽  
Christopher A. Klug
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Lineage ◽  
Cell Subset ◽  
Cell Development ◽  
B Cell Development ◽  
Thymocyte Development ◽  
Cell Stage ◽  
B1 B Cells

ABSTRACT Although studies have shown that the Notch2 family member is critical for embryonic development, little is known concerning its role in hematopoiesis. In this study, we show that the effects of an activated form of Notch2 (N2IC) on the T-cell lineage are dosage related. High-level expression of N2IC results in the development of T-cell leukemias. In contrast, lower-level expression of N2IC does not lead to transformation but skews thymocyte development to the CD8 lineage. Underlying this skew is a dramatic enhancement in positive selection and CD8SP maturation. N2IC permits early B-cell development but blocks the maturation of conventional B2 cells at the pre-B stage, which is the limit of endogenous Notch2 protein expression in developing B cells. Most strikingly, while B2 B cell development is blocked at the pre-B-cell stage, N2IC promotes the selective development of LPS-responsive B1 B cells. This study implicates a role for Notch2 in the maturation of the CD8 lineage and suggests a novel function for Notch2 in the development of the B1 B-cell subset.

Impaired T- and B-cell development in Tcl1-deficient mice

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 1288-1294 ◽  
Author(s):  
Sang-Moo Kang ◽  
Maria Grazia Narducci ◽  
Cristina Lazzeri ◽  
Adriana M. Mongiovì ◽  
Elisabetta Caprini ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Development ◽  
B Cell Development ◽  
Cell Stage ◽  
Marginal Zone B Cells ◽  
Induced Apoptosis ◽  
Deficient Mice

AbstractTCL1, the overexpression of which may result in T-cell leukemia, is normally expressed in early embryonic tissues, the ovary, and lymphoid lineage cells. Our analysis of mouse B-lineage cells indicates that Tcl1 expression is initiated in pro-B cells and persists in splenic marginal zone and follicular B cells. T-lineage Tcl1 expression begins in thymocyte progenitors, continues in CD4+CD8+ thymocytes, and is extinguished in mature T cells. In Tcl1-deficient mice, we found B lymphopoiesis to be compromised at the pre-B cell stage and T-cell lymphopoiesis to be impaired at the CD4+CD8+ thymocyte stage. A corresponding increase was observed in thymocyte susceptibility to anti-CD3ϵ–induced apoptosis. Reduced numbers of splenic follicular and germinal center B cells were accompanied by impaired production of immunoglobulin G1 (IgG1) and IgG2b antibodies in response to a T-dependent antigen. The marginal zone B cells and T-cell–independent antibody responses were also diminished in Tcl1-/- mice. This analysis indicates a significant role for Tcl1, a coactivator of Akt signaling, in normal T- and B-cell development and function.

scholarly journals CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation.

1996 ◽  
Vol 183 (4) ◽  
pp. 1707-1718 ◽  
Author(s):  
K F Byth ◽  
L A Conroy ◽  
S Howlett ◽  
A J Smith ◽  
J May ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cell ◽  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Cross Linking ◽  
Thymocyte Development ◽  
Double Positive

The CD45 transmembrane glycoprotein has been shown to be a protein phosphotyrosine phosphatase and to be important in signal transduction in T and B lymphocytes. We have employed gene targeting to create a strain of transgenic mice that completely lacks expression of all isoforms of CD45. The spleens from CD45-null mice contain approximately twice the number of B cells and one fifth the number of T cells found in normal controls. The increase in B cell numbers is due to the specific expansion of two B cell subpopulations that express high levels of immunoglobulin (IgM) staining. T cell development is significantly inhibited in CD45-null animals at two distinct stages. The efficiency of the development of CD4-CD8- thymocytes into CD4+ CD8+ thymocytes is reduced by twofold, subsequently the frequency of successful maturation of the double positive population into mature, single positive thymocytes is reduced by a further four- to fivefold. In addition, we demonstrate that CD45-null thymocytes are severely impaired in their apoptotic response to cross-linking signals via T cell receptor (TCR) in fetal thymic organ culture. In contrast, apoptosis can be induced normally in CD45-null thymocytes by non-TCR-mediated signals. Since both positive and negative selection require signals through the TCR complex, these findings suggest that CD45 is an important regulator of signal transduction via the TCR complex at multiple stages of T cell development. CD45 is absolutely required for the transmission of mitogenic signals via IgM and IgD. By contrast, CD45-null B cells proliferate as well as wild-type cells to CD40-mediated signals. The proliferation of B cells in response to CD38 cross-linking is significantly reduced but not abolished by the CD45-null mutation. We conclude that CD45 is not required at any stage during the generation of mature peripheral B cells, however its loss reveals a previously unrecognized role for CD45 in the regulation of certain subpopulations of B cells.

scholarly journals IL-7 receptor signaling is necessary for stage transition in adult B cell development through up-regulation of EBF

2005 ◽  
Vol 201 (8) ◽  
pp. 1197-1203 ◽  
Author(s):  
Kazu Kikuchi ◽  
Anne Y. Lai ◽  
Chia-Lin Hsu ◽  
Motonari Kondo
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
Target Genes ◽  
Cell Development ◽  
B Cell Development ◽  
Receptor Signaling ◽  
Cell Stage ◽  
Transcription Factor Network ◽  
Stage Transition

Cytokine receptor signals have been suggested to stimulate cell differentiation during hemato/lymphopoiesis. Such action, however, has not been clearly demonstrated. Here, we show that adult B cell development in IL-7−/− and IL-7Rα2/− mice is arrested at the pre–pro-B cell stage due to insufficient expression of the B cell–specific transcription factor EBF and its target genes, which form a transcription factor network in determining B lineage specification. EBF expression is restored in IL-7−/− pre–pro-B cells upon IL-7 stimulation or in IL-7Rα−/− pre–pro-B cells by activation of STAT5, a major signaling molecule downstream of the IL-7R signaling pathway. Furthermore, enforced EBF expression partially rescues B cell development in IL-7Rα−/− mice. Thus, IL-7 receptor signaling is a participant in the formation of the transcription factor network during B lymphopoiesis by up-regulating EBF, allowing stage transition from the pre–pro-B to further maturational stages.

scholarly journals Induction of metabolic quiescence defines the transitional to follicular B cell switch

2019 ◽  
Vol 12 (604) ◽  
pp. eaaw5573 ◽  
Author(s):  
Jocelyn R. Farmer ◽  
Hugues Allard-Chamard ◽  
Na Sun ◽  
Maimuna Ahmad ◽  
Alice Bertocchi ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Surface ◽  
B Cell ◽  
Cell Development ◽  
B Cell Development ◽  
Ampk Activation ◽  
Cell Stage ◽  
Extracellular Adenosine ◽  
Transitional B Cells ◽  
Follicular B Cells

Transitional B cells must actively undergo selection for self-tolerance before maturing into their resting follicular B cell successors. We found that metabolic quiescence was acquired at the follicular B cell stage in both humans and mice. In follicular B cells, the expression of genes involved in ribosome biogenesis, aerobic respiration, and mammalian target of rapamycin complex 1 (mTORC1) signaling was reduced when compared to that in transitional B cells. Functional metabolism studies, profiling of whole-cell metabolites, and analysis of cell surface proteins in human B cells suggested that this transition was also associated with increased extracellular adenosine salvage. Follicular B cells increased the abundance of the cell surface ectonucleotidase CD73, which coincided with adenosine 5′-monophosphate–activated protein kinase (AMPK) activation. Differentiation to the follicular B cell stage in vitro correlated with surface acquisition of CD73 on human transitional B cells and was augmented with the AMPK agonist, AICAR. Last, individuals with gain-of-function PIK3CD (PI3Kδ) mutations and increased pS6 activation exhibited a near absence of circulating follicular B cells. Together, our data suggest that mTORC1 attenuation may be necessary for human follicular B cell development. These data identify a distinct metabolic switch during human B cell development at the transitional to follicular stages, which is characterized by an induction of extracellular adenosine salvage, AMPK activation, and the acquisition of metabolic quiescence.

Interleukin-7 Over-Expression Regulates T Cell Versus B Cell Lineage Development in the Thymus.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3238-3238
Author(s):  
Nahed El Kassar ◽  
Philip J. Lucas ◽  
Frank Flomerfelt ◽  
Melinda Merchant ◽  
Catherine V. Bare ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Development ◽  
B Cell Development ◽  
Dose Effect ◽  
Proliferative Potential ◽  
Thymic Tissue ◽  
Over Expression ◽  
Normal Controls

Abstract We have shown that high IL-7 transgene (Tg) over-expression (39-fold at day 1 in thymic tissue) under the T cell specific, proximal lck promoter had a dose effect on TCRαβ that was accompanied by active B cell development in the thymus. To further characterize these affects in the thymus of IL-7 transgenic mice, we analyzed thymi from day 18 embryos and newborn Tg mice, as well as fetal thymic organ culture (FTOC) derived from using day 16 embryos. We show that arrested T-cell and increased B-cell thymic development is initiated during fetal development. Using mixed bone marrow chimeras and anti-IL-7 monoclonal antibody injection, we further demonstrate that abnormalities in thymic T and B cell development are non-cell autonomous and are due to IL-7 over-expression. Recently, it was shown that only the early thymocyte progenitor (ETP, c-kit+IL-7R−/lo) fraction within the DN1 subpopulation had a T-cell proliferative potential in contrast to the c-kit−IL-7R+ DN1 subset. Here we show that in Tg mice the ETPs were decreased, while the c-kit−IL-7R+ cells are increased in both percentage and absolute count when compared to normal controls. In order to explore the T vs. B ETP potential, we seeded re-aggregate thymic organ cultures with sorted lin−CD44+CD25−c-kit+IL-7R+ cells. While ETPs derived from normal controls were able to proliferate and produce 83% of DP thymocytes, ETPs sorted from Tg mice developed poorly (10-fold less) into DP cells (30%) and produced 14% of B220+ cells vs. 6% in controls. Moreover, sorted Pro/Pre B derived thymic B cells from Tg mice, but not BM-derived Pro/Pre B cells had the TCRβD-J rearrangement, suggesting a T-specific origin. Since the B-cell differentiation pathway in normal mice is selectively inhibited by thymic presentation of Notch ligands, we hypothesized that IL-7 down-regulates Notch signaling. To test this hypothesis, we analyzed thymocyte progenitors (DN1-DN4) in normal and Tg mice for the intra-cytoplasmic part of Notch, that is cleaved upon Notch/Notch-ligand activation. Notch staining was decreased in the lin−CD44+CD25inter representing the only DN2 population present in these Tg mice. These data favour a decrease of Notch signalling in mice with high IL-7 Tg over-expression, inducing a block in TCRαβ development, and skewing of thymic B cell development by T vs. B lineage subversion. These conclusions may have implications for IL-7 in the clinical setting.

The Proto-Oncogene LRF Is Essential for Normal Mature B Cell Development and Germinal Center Formation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1788-1788
Author(s):  
Nagisa Sakurai ◽  
Manami Maeda ◽  
Sung-UK Lee ◽  
Julie Teruya-Feldstein ◽  
Takahiro Maeda
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Development ◽  
B Cell Development ◽  
Cell Stage ◽  
Transitional B Cells ◽  
Notch Pathways ◽  
Secondary Lymphoid Organs

Abstract LRF (Leukemia/Lymphoma Related Factor, also known as Pokemon, FBI-1, OCZF and ZBTB7a) was originally identified as an interaction partner of the oncoprotein BCL6. LRF can act as a proto-oncogene by repressing the tumor suppressor ARF and cooperates with BCL6 in MEF (mouse embryonic fibroblasts) immortalization. It is highly expressed in human Non-Hodgkin Lymphoma (NHL) cases, in the pathogenesis of which BCL6 is known to be involved (Maeda et al. Nature 2005). Inducible inactivation of the LRF gene in mouse Hematopoietic Stem Cells (HSCs) results in complete block of early B cell development at the HSC/progenitor stages and concomitant development of double positive (DP) T cells in the bone marrow (BM) (Maeda et al. Science 2007). While these findings clearly illustrate key roles of LRF in normal and malignant B cell development, it is not fully identified as to which B cell stages LRF is required during normal B cell development. To elucidate the role of LRF in B cells in vivo, we established and characterized B cell-specific LRF conditional knockout (KO) mice. We took advantage of mb-1 Cre knock-in mice, in which Cre expression is restricted to the B cells after the ProB cell stage. B cell compartments in the BM (PreProB, ProB, PreB and immatureB) are grossly normal in LRFF/ Fmb1-Cre mice. The LRF gene was efficiently eliminated in BM CD19+ B cells revealed by quantitative real-time PCR assay. Furthermore, LRF protein was not detected in purified CD19+ B cells, but seen in CD19-non-B cells, confirming the specific inactivation of the LRF gene in B cells. Thus, despite its critical role at the HSC/progenitor stages, LRF was found to be dispensable for the survival of normal BM B cells. These findings are consistent with the fact that GSI treatment (Maeda et al. Science 2007) or Notch1 loss (Lee and Maeda, unpublished) rescues the defects in early B cell development seen in LRFF/FMx1-Cre+ mice. Notch signaling is necessary for the transitional B cells to commit to the marginal zone B cells (MZB). Inactivation of the component of the Notch pathways in mice results in no MZB development. On the contrary, deletion of the MINT/SHARP gene, a suppressor of Notch signaling, leads to increase of MZB cells and concomitant reduction of follicular B (FOB) cells, indicating that Notch induces MZB cell fate at the transitional B cell stage. Given that LRF is a potent Notch suppressor at the HSC/progenitor stages, we hypothesized that LRF opposes Notch pathway in mature B cells as well. To test this hypothesis, we characterized mature B cell development in LRFF/Fmb1-Cre mice. While transitional B cells were largely unaffected in LRFF/Fmb1-Cre mice, we observed a slight but statistically significant reduction of follicular (FO) B cells (B220+CD19+AA4.1-CD1d-CD23+) and concomitant increase of MZB cells (B220+CD19+AA4.1-CD1d+CD23-) as seen in MINT/SHARP knockout mice. Thus, LRF may also oppose Notch pathways at the branching point for the FOB vs. MZB fate decision. Finally, to determine the role of LRF in Germinal Center (GC) formation in vivo, we characterized secondary lymphoid organs of LRFF/Fmb1-Cre mice after antigen stimulation. Both spleen and Peyer’s Patches were analyzed two weeks after immunization with Chicken Gamma Globulin (NP-CGG). While a GC reaction was robustly induced in control mice upon immunization, GC formation was significantly impaired in LRFF/Fmb1-Cre mice as revealed by immuno-histochemical analysis (IHC) and FACS. Only few GC cells (B220+CD19+FAS+CD38-PNA+) were observed in spleens, and the absolute numbers of GC cells were drastically reduced in LRFF/Fmb1-Cre mice. Residual LRF-deficient GC B cells were mostly negative for CXCR4, which is predominantly expressed in proliferating centroblasts within GCs, suggesting that LRF-deficient GC B cells may have defects in cellular proliferation in response to antigen stimuli. Our data indicates that LRF plays key roles in mature B cell development in the secondary lymphoid organs, but dispensable for the maintenance of early BM B cells.

scholarly journals bcl-x exhibits regulated expression during B cell development and activation and modulates lymphocyte survival in transgenic mice.

1996 ◽  
Vol 183 (2) ◽  
pp. 381-391 ◽  
Author(s):  
D A Grillot ◽  
R Merino ◽  
J C Pena ◽  
W C Fanslow ◽  
F D Finkelman ◽  
...  
Keyword(s):  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
Cell Lineage ◽  
Cell Development ◽  
B Cell Development ◽  
Immunoglobulin M ◽  
Protective Mechanism ◽  
And Function ◽  
Peripheral B Cells

We have assessed during B cell development, the regulation and function of bcl-x, a member of the bcl-2 family of apoptosis regulatory genes. Here we show that Bcl-xL, a product of bcl-x, is expressed in pre-B cells but downregulated at the immature and mature stages of B cell development. Bcl-xL but not Bcl-2 is rapidly induced in peripheral B cells upon surface immunoglobulin M (IgM) cross-linking, CD40 signaling, or LPS stimulation. Transgenic mice that overexpressed Bcl-xL within the B cell lineage exhibited marked accumulation of peripheral B cells in lymphoid organs and enhanced survival of developing and mature B cells. B cell survival was further increased by simultaneous expression of bcl-xL and bcl-2 transgenes. These studies demonstrate that Bcl-2 and Bcl-xL are regulated differentially during B cell development and activation of mature B cells. Induction of Bcl-xL after signaling through surface IgM and CD40 appears to provide mature B cells with an additional protective mechanism against apoptotic signals associated with antigen-induced activation and proliferation.

scholarly journals Essential role of EBF1 in the generation and function of distinct mature B cell types

2012 ◽  
Vol 209 (4) ◽  
pp. 775-792 ◽  
Author(s):  
Bojan Vilagos ◽  
Mareike Hoffmann ◽  
Abdallah Souabni ◽  
Qiong Sun ◽  
Barbara Werner ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Intracellular Signaling ◽  
Ectopic Expression ◽  
Cell Types ◽  
Cell Development ◽  
B Cell Development ◽  
Cell Stage ◽  
Cell Immunity ◽  
Cell Commitment

The transcription factor EBF1 is essential for lineage specification in early B cell development. In this study, we demonstrate by conditional mutagenesis that EBF1 is required for B cell commitment, pro–B cell development, and subsequent transition to the pre–B cell stage. Later in B cell development, EBF1 was essential for the generation and maintenance of several mature B cell types. Marginal zone and B-1 B cells were lost, whereas follicular (FO) and germinal center (GC) B cells were reduced in the absence of EBF1. Activation of the B cell receptor resulted in impaired intracellular signaling, proliferation and survival of EBF1-deficient FO B cells. Immune responses were severely reduced upon Ebf1 inactivation, as GCs were formed but not maintained. ChIP- and RNA-sequencing of FO B cells identified EBF1-activated genes that encode receptors, signal transducers, and transcriptional regulators implicated in B cell signaling. Notably, ectopic expression of EBF1 efficiently induced the development of B-1 cells at the expense of conventional B cells. These gain- and loss-of-function analyses uncovered novel important functions of EBF1 in controlling B cell immunity.

scholarly journals Increased Frequency of Pre–Pro B Cells in the Bone Marrow of New Zealand Black (NZB) Mice: Implications for aDevelopmental Block in B Cell Differentiation

2002 ◽  
Vol 9 (1) ◽  
pp. 35-45 ◽  
Author(s):  
Zhe-Xiong Lian ◽  
Hiroto Kita ◽  
Tomoyuki Okada ◽  
Tom Hsu ◽  
Leonard D. Shultz ◽  
...  
Keyword(s):  
New Zealand ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
B Cell Differentiation ◽  
Differentiation Markers ◽  
Cell Stage

Reductions in populations of both Pre-B cell (Hardy fractions D) and Pro-B cells (Hardy fractions B–C) have been described in association with murine lupus. Recent studies of B cell populations, based on evaluation of B cell differentiation markers, now allow the enumeration and enrichment of other stage specific precursor cells. In this study we report detailed analysis of the ontogeny of B cell lineage subsets in New Zealand black (NZB) and control strains of mice. Our data suggest that B cell development in NZB mice is partially arrested at the fraction A Pre–Pro B cell stage. This arrest at the Pre-Pro B cell stage is secondary to prolonged lifespan and greater resistance to spontaneous apoptosis. In addition, expression of the gene encoding the critical B cell development transcription factor BSAP is reduced in the Pre–Pro B cell stage in NZB mice. This impairment may influence subsequent B cell development to later stages, and thereby accounts for the down-regulation of the B cell receptor componentIgα(mb-1). Furthermore, levels of expression of theRug2, λ5andIgβ(B29) genes are also reduced in Pre–Pro B cells of NZB mice. The decreased frequency of precursor B cells in the Pre–Pro B cell population occurs at the most primitive stage of B cell differentiation.

scholarly journals Long noncoding RNAs in B-cell development and activation

Blood ◽  
2016 ◽  
Vol 128 (7) ◽  
pp. e10-e19 ◽  
Author(s):  
Tiago F. Brazão ◽  
Jethro S. Johnson ◽  
Jennifer Müller ◽  
Andreas Heger ◽  
Chris P. Ponting ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Cell Lineage ◽  
Noncoding Rnas ◽  
Cell Development ◽  
B Cell Development ◽  
Long Noncoding Rnas ◽  
Human B Cells

AbstractLong noncoding RNAs (lncRNAs) are potentially important regulators of cell differentiation and development, but little is known about their roles in B lymphocytes. Using RNA-seq and de novo transcript assembly, we identified 4516 lncRNAs expressed in 11 stages of B-cell development and activation. Most of these lncRNAs have not been previously detected, even in the closely related T-cell lineage. Comparison with lncRNAs previously described in human B cells identified 185 mouse lncRNAs that have human orthologs. Using chromatin immunoprecipitation-seq, we classified 20% of the lncRNAs as either enhancer-associated (eRNA) or promoter-associated RNAs. We identified 126 eRNAs whose expression closely correlated with the nearest coding gene, thereby indicating the likely location of numerous enhancers active in the B-cell lineage. Furthermore, using this catalog of newly discovered lncRNAs, we show that PAX5, a transcription factor required to specify the B-cell lineage, bound to and regulated the expression of 109 lncRNAs in pro-B and mature B cells and 184 lncRNAs in acute lymphoblastic leukemia.

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