The MAML1 Transcriptional Co-Activator Is Required for the Development of Marginal Zone B Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 777-777
Author(s):  
Lizi Wu ◽  
Ivan Maillard ◽  
Makoto Nakamura ◽  
Warren S. Pear ◽  
James D. Griffin
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
T Cell Development ◽  
Cell Development ◽  
Notch Receptor ◽  
Lymphoid Cells ◽  
Marginal Zone B Cells ◽  
Notch Receptors

Abstract Notch1 and Notch2 receptor-mediated signaling appear to have important and unique roles in lymphoid lineage commitment. Notch1 is required for T cell development, while Notch2 is essential for marginal zone B cell development. This specificity is not completely explained by differential expression patterns of Notch1 and 2 or Notch ligands, suggesting that there are other genes that contribute to specifying Notch receptor functions. We have previously shown that the MAML family of transcriptional co-activators is essential for Notch-induced transcriptional events, and functions by forming ternary complexes with Notch and the transcription factor CSL in the nucleus. This MAML family currently consists of three members, MAML1-3, all of which can function as co-activators for Notch receptors in vitro . In this study, we investigated the possibility that MAML1 co-activator contributes to determining Notch receptor function by generating mice deficient in the Maml1 gene. Maml1 -deficient mice fail to thrive and die within 10 days of birth. The morphology of marrow, nodes, and spleen was grossly intact. The ability of Maml1-deficient stem cells to generate different T and B lineages of lymphoid cells was determined by transplanting fetal liver cells isolated from E14.5 embryos into lethally irradiated wild-type recipient mice and analyzing donor-derived lymphoid cells 12 weeks post-transplantation. We found that the deletion of Maml1 results in complete loss of marginal zone B cell lineage (MZB, defined by B220+CD21hiCD23lo). Moreover, the number of MZB cells was reduced to about 50% in Maml1 -heterozygous fetal liver chimeras as compared to wild type controls. However, T cell development was largely unaffected, with only a modest but significant increase in the number of γδ T cells (about 2 fold) in both the thymus and the spleen. Therefore, these results suggest the unexpected finding that targeted deletion of Maml1 in hematopoietic cells is similar to the targeted deletion of either Notch2 or the Notch ligand, Delta-like 1 (Dll1) resulting in the loss of marginal zone B cells and minimal effects on T cell development. Moreover, the number of marginal zone B cells is correlated with Maml1 gene dosage, indicating haploinsufficiency. These data suggest that the Notch ligand Dll1 activates Notch2 signaling resulting in a Notch2/MAML1/CSL complex that is essential for marginal zone B cell development. Further studies with respect to relative expression levels of various MAML genes and interactions of MAML co-activators and Notch receptors may shed additional light into understanding how different Notch receptors regulate cell fate decisions in hematopoiesis.

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 Morphologic and Functional Effects of Gamma Secretase Inhibition on Splenic Marginal Zone B Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Maria Cristina de Vera Mudry ◽  
Franziska Regenass-Lechner ◽  
Laurence Ozmen ◽  
Bernd Altmann ◽  
Matthias Festag ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Nuclear Translocation ◽  
Recovery Period ◽  
Functional Characterization ◽  
Notch Receptor ◽  
Marginal Zone B Cells ◽  
Cell Fate Decisions

Theγ-secretase complex is a promising target in Alzheimer’s disease because of its role in the amyloidogenic processing ofβ-amyloid precursor protein. This enzyme also catalyzes the cleavage of Notch receptor, resulting in the nuclear translocation of intracellular Notch where it modulates gene transcription. Notch signaling is essential in cell fate decisions during embryogenesis, neuronal differentiation, hematopoiesis, and development of T and B cells, including splenic marginal zone (MZ) B cells. This B cell compartment participates in the early phases of the immune response to blood-borne bacteria and viruses. Chronic treatment with the oralγ-secretase inhibitor RO4929097 resulted in dose-dependent decreased cellularity (atrophy) of the MZ of rats and mice. Significant decreases in relative MZ B-cell numbers of RO4929097-treated animals were confirmed by flow cytometry. Numbers of MZ B cells reverted to normal after a sufficient RO4929097-free recovery period. Functional characterization of the immune response in relation to RO4929097-related MZ B cell decrease was assessed in mice vaccinated with inactivated vesicular stomatitis virus (VSV). Compared with the immunosuppressant cyclosporin A, RO4929097 caused only mild and reversible delayed early neutralizing IgM and IgG responses to VSV. Thus, the functional consequence of MZ B cell decrease on host defense is comparatively mild.

Marginal Zone B Cells Mediate a CD4 T Cell Dependent Extrafollicular Antibody Response Following RBC Transfusion in Mice

Blood ◽  
2021 ◽  
Author(s):  
Patricia E Zerra ◽  
Seema R Patel ◽  
Ryan Philip Jajosky ◽  
Connie M Arthur ◽  
James W McCoy ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Antibody Response ◽  
B Cell ◽  
T Cell Activation ◽  
Antibody Formation ◽  
Marginal Zone ◽  
Cd4 T Cell ◽  
Marginal Zone B Cells ◽  
Rbc Transfusion

Red blood cell (RBC) transfusions can result in alloimmunization toward RBC alloantigens that can increase the probability of complications following subsequent transfusion. An improved understanding of the immune mechanisms that underlie RBC alloimmunization is critical if future strategies capable of preventing or even reducing this process are to be realized. Using the HOD (hen egg lysozyme and ovalbumin fused to human Duffy) model system, we aimed to identify initiating immune factors that may govern early anti-HOD alloantibody formation. Our findings demonstrate that HOD RBCs continuously localize to the marginal sinus following transfusion, where they co-localize with marginal zone (MZ) B cells. Depletion of MZ B cells inhibited IgM and IgG anti-HOD antibody formation, while CD4 T cell depletion only prevented IgG anti-HOD antibody development. HOD-specific CD4 T cells displayed similar proliferation and activation following transfusion of HOD RBCs into wild type or MZ B cell deficient recipients, suggesting that IgG formation is not dependent on MZ B cell-mediated CD4 T cell activation. Moreover, depletion of follicular B cells failed to substantially impact the anti-HOD antibody response and no increase in antigen specific germinal center B cells was detected following HOD RBC transfusion, suggesting that antibody formation is not dependent on the splenic follicle. Despite this, anti-HOD antibodies persisted for several months following HOD RBC transfusion. Overall, these data suggest MZ B cells can initiate and then contribute to RBC alloantibody formation, highlighting a unique immune pathway that can be engaged following RBC transfusion.

scholarly journals Autoreactive marginal zone B cells are spontaneously activated but lymph node B cells require T cell help

2006 ◽  
Vol 203 (8) ◽  
pp. 1985-1998 ◽  
Author(s):  
Laura Mandik-Nayak ◽  
Jennifer Racz ◽  
Barry P. Sleckman ◽  
Paul M. Allen
Keyword(s):  
Lymph Node ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
B Cell Tolerance ◽  
Marginal Zone B Cells ◽  
T Cell Help

In K/BxN mice, arthritis is induced by autoantibodies against glucose-6-phosphate-isomerase (GPI). To investigate B cell tolerance to GPI in nonautoimmune mice, we increased the GPI-reactive B cell frequency using a low affinity anti-GPI H chain transgene. Surprisingly, anti-GPI B cells were not tolerant to this ubiquitously expressed and circulating autoantigen. Instead, they were found in two functionally distinct compartments: an activated population in the splenic marginal zone (MZ) and an antigenically ignorant one in the recirculating follicular/lymph node (LN) pool. This difference in activation was due to increased autoantigen availability in the MZ. Importantly, the LN anti-GPI B cells remained functionally competent and could be induced to secrete autoantibodies in response to cognate T cell help in vitro and in vivo. Therefore, our study of low affinity autoreactive B cells reveals two distinct but potentially concurrent mechanisms for their activation, of which one is T cell dependent and the other is T cell independent.

Notch Activation Converts B Cells into a T Cell Fate at the Earliest Stages of B Cell Committed Progenitors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3151-3151
Author(s):  
Jalal Taneera ◽  
Emma Smith ◽  
Mikael Sigvardsson ◽  
Emil Hansson ◽  
Urban Lindahl ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
T Cell Development ◽  
Cell Development ◽  
Cell Stage ◽  
Cell Commitment ◽  
Notch Activation

Abstract Notch activation has been suggested to promote T cell development at the expense of B cell commitment at the level of a common lymphoid progenitor prior to B cell commitment. Here, we explored the possibility that Notch activation might be able to switch the fate of already committed B cell progenitors towards T cell development upon Notch activation. To address this we overexpressed constitutively activated Notch-3 (N3IC) in B cell progenitors purified from transgenic mice in which human CD25 is expressed under control of the λ5 promoter. Strikingly, whereas untransduced and control transduced B220+λ5+CD3− B cell progenitors gave rise exclusively to B cells, CD4+ and CD8+ T cells but no B cells were derived from N3IC-transduced cells when transplanted into sublethally irradiated NOD-SCID mice. Gene expression profiling demonstrated that untransduced B220+ λ5+CD3− B cell progenitors expressed λ5 and CD19 but not the T cell specific genes GATA-3, lck and pTα, whereas CD3+ T cells derived from N3IC-transduced B220+λ5+CD3−cells failed to express λ5 and CD19, but were positive for GATA-3, lck and pTα expression as well as a and b T cell rearrangement. Furthermore, DJ rearrangements were detected at very low levels in CD3+ cells isolated from normal non-transduced BM, but were more abundant in the N3IC-transduced CD3+ BM cells. Noteworthy, N3IC-transduced B220+λ5+CD3−CD19+ proB cell progenitors failed to generate B as well as T cells, whereas N3IC-transduced B220+λ5+CD3−CD19− pre-proB cells produced exclusively T cells, even when evaluated at low cell numbers. In conclusion Notch activation can switch committed B cell progenitors from a B cell to a T cell fate, but this plasticity is lost at the Pro-B cell stage, upon upregulation of CD19 expression.

T and B cell development in pituitary deficient insulin-like growth factor-II transgenic dwarf mice

1997 ◽  
Vol 155 (1) ◽  
pp. 165-170 ◽  
Author(s):  
R Kooijman ◽  
SC van Buul-Offers ◽  
LE Scholtens ◽  
RG Reijnen-Gresnigt ◽  
BJ Zegers
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Bone Marrow Cells ◽  
T Cell Development ◽  
Cell Development ◽  
B Cell Development ◽  
Igf I ◽  
Dwarf Mice

Treatment of mice with IGF-I stimulates T and B cell development. We showed that overexpression of IGF-II in transgenic FVB/N mice only stimulated T cell development. In the present study, we further addressed the in vivo effects of IGF-II in the absence of IGF-I to get more insight into the potential abilities of IGF-II to influence T and B cell development. To this end, we studied lymphocyte development in IGF-II transgenic Snell dwarf mice that are prolactin, GH and thyroid-stimulating hormone deficient and as a consequence show low serum IGF-I levels. We showed that T cell development was stimulated to the same extent as in IGF-II transgenic FVB/N mice. Furthermore, IGF-II increased the number of nucleated bone marrow cells and the number of immature B cells without having an effect on the number of mature B cells in spleen and bone marrow. Our data show that IGF-II has preferential effects on T cell development compared with B development, and that these preferential effects also occur in the absence of measurable IGF-I levels.

Perturbation of B-cell development in mice overexpressing the Bcl-2 homolog A1

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3350-3359 ◽  
Author(s):  
Peter I. Chuang ◽  
Samantha Morefield ◽  
Chien-Ying Liu ◽  
Stephen Chen ◽  
John M. Harlan ◽  
...  
Keyword(s):  
Immune System ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
System Development ◽  
Cell Development ◽  
B Cell Development ◽  
Lymphoid Cells ◽  
Immune System Development ◽  
And Function

Abstract Decisions about cell survival or death are central components of adaptive immunity and occur at several levels in immune system development and function. The Bcl-2 family of homologous proteins plays an important role in these decisions in lymphoid cells. Bcl-2, Bcl-xL, and A1 are differentially expressed during B- and T-cell development, and they have shared and distinct roles in regulating cell death. We sought to gain insight into the role of A1 in immune system development and function. A murine A1-a transgene was expressed under the control of the Eμ enhancer, and mice with A1 overexpression in B- and T-cell lineages were derived. Thymocytes and early B cells in Eμ-A1 mice showed extended survival. B-lineage development was altered, with expansion of the pro–B cell subset at the expense of pre–B cells, suggesting an impairment of the pro– to pre–B-cell transition. This early B-cell phenotype resembled Eμ–Bcl-xL mice but did not preferentially rescue cells with completed V(D)J rearrangements of the immunoglobulin heavy chain. In contrast to Eμ–Bcl-2 transgenes, A1 expression in pro–B cells did not rescue pre–B-cell development in SCID mice. These studies indicate that A1 protects lymphocytes from apoptosis in vitro but that it has lineage- and stage-specific effects on lymphoid development. Comparison with the effects of Bcl-2 and Bcl-xL expressed under similar control elements supports the model that antiapoptotic Bcl-2 homologs interact differentially with intracellular pathways affecting development and apoptosis in lymphoid cells.

scholarly journals Essential requirement for nicastrin in marginal zone and B-1 B cell development

2020 ◽  
Vol 117 (9) ◽  
pp. 4894-4901 ◽  
Author(s):  
Jin Huk Choi ◽  
Jonghee Han ◽  
Panayotis C. Theodoropoulos ◽  
Xue Zhong ◽  
Jianhui Wang ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Missense Mutation ◽  
Marginal Zone ◽  
T Cell Development ◽  
Cell Development ◽  
B Cell Development ◽  
Causative Mutation ◽  
Acne Inversa ◽  
Essential Requirement

γ-secretase is an intramembrane protease complex that catalyzes the proteolytic cleavage of amyloid precursor protein and Notch. Impaired γ-secretase function is associated with the development of Alzheimer’s disease and familial acne inversa in humans. In a forward genetic screen of mice withN-ethyl-N-nitrosourea-induced mutations for defects in adaptive immunity, we identified animals within a single pedigree exhibiting both hypopigmentation of the fur and diminished T cell-independent (TI) antibody responses. The causative mutation was inNcstn, an essential gene encoding the protein nicastrin (NCSTN), a member of the γ-secretase complex that functions to recruit substrates for proteolysis. The missense mutation severely limits the glycosylation of NCSTN to its mature form and impairs the integrity of the γ-secretase complex as well as its catalytic activity toward its substrate Notch, a critical regulator of B cell and T cell development. Strikingly, however, this missense mutation affects B cell development but not thymocyte or T cell development. TheNcstnallele uncovered in these studies reveals an essential requirement for NCSTN during the type 2 transitional-marginal zone precursor stage and peritoneal B-1 B cell development, the TI antibody response, fur pigmentation, and intestinal homeostasis in mice.

Driving T Cell Development in the Thymus.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3860-3860
Author(s):  
Cristina M. Joao ◽  
Brenda M. Ogle ◽  
Marilia Cascalho ◽  
Jeffrey L. Platt
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Thymic Epithelial Cells ◽  
P Value ◽  
Tcr Repertoire ◽  
Repertoire Diversity ◽  
Deficient Mice

Abstract Background: Classic reports on lymphocyte development hold that B and T cells develop independently. This concept derives in part from the observation that patients with pure B cell immunodeficiency and hypogammaglobulinemia have a normal thymus and T cell numbers. Our recent findings however challenge this concept. We found that T cell development depends not only on the interaction of T cell precursors with thymic epithelial cells but also on other cells. Here we report that those other cells are B cells. Aims: The purpose of this study was to determine whether B cells drive T cell development and TCR diversification in the thymus. Methods: We compared the number of sub-populations of thymocytes and TCR repertoire diversity in B-cell deficient and B-cell proficient mice and in B cell deficient mice following immunoglobulin (Ig) injections. Total leucocytes numbers were determined with a Coulter counter and numbers of thymocytes sub-populations were calculated by flow cytometry analysis. TCR repertoire diversity was measured by a novel method based on hybridization of TCR Vβ specific cRNA on a gene chip platform. Results: In B-cell deficient mice the number of thymocytes was four times reduced and TCR Vβ chain diversity was up to one million times lower compared with wild type mice. Numbers and diversity were restored by treatment of the mice with gamma globulin (see table). Conclusions: T cell development and diversification is driven by B cells. Mice Number of total thymocytes (mean ± standard deviation) p Value β V TCR diversity of thymocytes (median; min.-max.) p Value C57BL/6 (wild mice) 1.3 x 108 ± 5.1 x 107N=7 4.7 x 106; 1.0 x 105 − 1.1 x 108N=5 JH−/− (B cell immunodeficient mice) 3.1 x 107 ± 1.7 x107N=7 0.002 5.9 x 102; 3.6 x 102 − 1.1 x 103N=5 0.0002 JH−/− treated with Ig 3.9 x 107 ± 1.4 x106N=2 0.20 1.1 x 105; 2.7 x 100 − 7.7 x 105N=4 0.08

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