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 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.

scholarly journals Wiskott-Aldrich syndrome protein (WASP) and N-WASP are critical for peripheral B-cell development and function

Blood ◽  
2012 ◽  
Vol 119 (17) ◽  
pp. 3966-3974 ◽  
Author(s):  
Lisa S. Westerberg ◽  
Carin Dahlberg ◽  
Marisa Baptista ◽  
Christopher J. Moran ◽  
Cynthia Detre ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Development ◽  
B Cell Development ◽  
Wild Type ◽  
And Function ◽  
Syndrome Protein

Abstract The Wiskott-Aldrich syndrome protein (WASP) is a key cytoskeletal regulator of hematopoietic cells. Although WASP-knockout (WKO) mice have aberrant B-cell cytoskeletal responses, B-cell development is relatively normal. We hypothesized that N-WASP, a ubiquitously expressed homolog of WASP, may serve some redundant functions with WASP in B cells. In the present study, we generated mice lacking WASP and N-WASP in B cells (conditional double knockout [cDKO] B cells) and show that cDKO mice had decreased numbers of follicular and marginal zone B cells in the spleen. Receptor-induced activation of cDKO B cells led to normal proliferation but a marked reduction of spreading compared with wild-type and WKO B cells. Whereas WKO B cells showed decreased migration in vitro and homing in vivo compared with wild-type cells, cDKO B cells showed an even more pronounced decrease in the migratory response in vivo. After injection of 2,4,6-trinitrophenol (TNP)–Ficoll, cDKO B cells had reduced antigen uptake in the splenic marginal zone. Despite high basal serum IgM, cDKO mice mounted a reduced immune response to the T cell–independent antigen TNP-Ficoll and to the T cell–dependent antigen TNP–keyhole limpet hemocyanin. Our results reveal that the combined activity of WASP and N-WASP is required for peripheral B-cell development and function.

The POZ/BTB Domain Transcription Factor Miz-1 (Zbtb17) Is Required during Early B Cell Development for the Survival of B-Cell Progenitors and Is Essential for the Formation of Mature Follicular B Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 703-703
Author(s):  
Christian Kosan ◽  
Tarik Moroy
Keyword(s):  
Bone Marrow ◽  
Transcription Factor ◽  
B Cells ◽  
B Cell ◽  
Cell Development ◽  
B Cell Development ◽  
Marginal Zone B Cells ◽  
Btb Domain ◽  
Follicular B Cells ◽  
Deficient Mice

Abstract B-cell development takes place in the bone marrow and is defined by a number of sequential steps that include the up-regulation of CD19, the rearrangement of immunoglobulin heavy and light chain genes (V(D)J recombination) and the expression of surface immunoglobulin. The early steps are regulated by cytokine signaling and the hierarchical expression of transcription factors, among them EBF, Pax5 and E2A and any interference with these critical elements leads to partial or total abrogation of B cell development. Here we present evidence that the POZ/BTB domain transcription factor Miz-1 (Zbtb17) represents an important novel regulator of the early development of follicular B cells. We have used gene targeting in mice to generate a non-functional allele of Miz-1 in all hematopoietic cells. In these mice, the development of adult follicular B cells is almost entirely abrogated, whereas the formation of marginal zone B-cells remain unaffected. Miz-1 deficiency correlated with the absence of CD19+ pro B-cells from the bone marrow and a block at the transition of the pre-pro-B cell to the pro-B cell stage. Although common lymphoid progenitors (CLPs) that are at the origin of B-cell development were present in Miz-1 deficient mice, they showed decreased expression of E2A, EBF and Pax5 compared to their wild type counterparts. Moreover, they were unable to differentiate in culture into more mature B cells even on stroma cells (OP9) and the presence or absence of IL-7. Interestingly, a forced expression of EBF or PAX5 in Miz-1 deficient progenitor cells did not rescue this phenotype. Furthermore, fetal B cell development, which has been shown to depend on EBF and Pax5, is not altered in Miz-1 deficient mice, suggesting that Miz-1 acts in a pathway that is independent of these critical B-cell regulators. In contrast, however, to EBF and Paxc5, the co-expression of a Bcl-2 transgene almost completely restored the development of more mature CD19+ or IgM+ B-cells in Miz-1 deficient mice. This indicated that Miz-1 is implicated in the regulation of cell survival at early stages of B cell development. Since it has been shown before that Bcl-2 is a downstream effector of Miz-1, it is conceivable that Miz-1 regulates Bcl-2 in the early B cell precursors, possibly as an element of the IL-7 signaling pathway, and thereby ensures their survival and proper development. We conclude that Miz-1 represents a novel regulator of early B cell development that exerts its function at a precise step in adult mice independently of other well-established regulators of B-cell development such as EBF or Pax5.

scholarly journals Interference with Immunoglobulin (Ig)α Immunoreceptor Tyrosine–Based Activation Motif (Itam) Phosphorylation Modulates or Blocks B Cell Development, Depending on the Availability of an Igβ Cytoplasmic Tail

2001 ◽  
Vol 194 (4) ◽  
pp. 455-470 ◽  
Author(s):  
Manfred Kraus ◽  
Lily I. Pao ◽  
Amy Reichlin ◽  
Yun Hu ◽  
Beth Canono ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
Calcium Flux ◽  
Cell Stage ◽  
Marginal Zone B Cells ◽  
Receptor Ligation ◽  
Activation Motif

To determine the function of immunoglobulin (Ig)α immunoreceptor tyrosine–based activation motif (ITAM) phosphorylation, we generated mice in which Igα ITAM tyrosines were replaced by phenylalanines (IgαFF/FF). IgαFF/FFmice had a specific reduction of B1 and marginal zone B cells, whereas B2 cell development appeared to be normal, except that λ1 light chain usage was increased. The mutants responded less efficiently to T cell–dependent antigens, whereas T cell–independent responses were unaffected. Upon B cell receptor ligation, the cells exhibited heightened calcium flux, weaker Lyn and Syk tyrosine phosphorylation, and phosphorylation of Igα non-ITAM tyrosines. Strikingly, when the Igα ITAM mutation was combined with a truncation of Igβ, B cell development was completely blocked at the pro-B cell stage, indicating a crucial role of ITAM phosphorylation in B cell development.

scholarly journals Single and Combined Deletions of the NTAL/LAB and LAT Adaptors Minimally Affect B-Cell Development and Function

2005 ◽  
Vol 25 (11) ◽  
pp. 4455-4465 ◽  
Author(s):  
Ying Wang ◽  
Ondrej Horvath ◽  
Andrea Hamm-Baarke ◽  
Mireille Richelme ◽  
Claude Grégoire ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Development ◽  
B Cell Development ◽  
And Function ◽  
Deficient Mice

ABSTRACT NTAL (non-T-cell activation linker, also called LAB) and LAT (linker for activation of T cells) are evolutionarily related transmembrane adaptor proteins that are phosphorylated upon immunoreceptor engagement. Using quantitative reverse transcription-PCR, both NTAL and LAT were found to be expressed in B cells. However, LAT expression was limited to early B cells, whereas NTAL expression typified mature B cells. To delineate their roles in B-cell development and function, Ntal-deficient mice were generated and crossed with Lat-deficient mice. B cells developed in Lat −/− Ntal −/− double-deficient mice and in mice lacking either of the two adaptors with the same efficiency as in wild-type mice. Upon B-cell antigen receptor cross-linking, Ntal −/− B cells exhibited slightly increased Ca2+ mobilization and proliferation. In addition, Ntal-deficient mice had increased levels of natural antibodies and slightly increased humoral response to a T-dependent antigen. Normal titers of serum-specific immunoglobulins were produced in response to a T-cell-independent antigen. Although NTAL is also expressed in plasma cells, its absence did not affect the hypergammaglobulinemia E and G1 that developed in mice with a mutation in tyrosine 136 of LAT. Therefore, NTAL does not play a role in B cells symmetric to the role played by LAT in T cells.

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.

Vav proteins regulate peripheral B-cell survival

Blood ◽  
2005 ◽  
Vol 106 (7) ◽  
pp. 2391-2398 ◽  
Author(s):  
Elena Vigorito ◽  
Laure Gambardella ◽  
Francesco Colucci ◽  
Simon McAdam ◽  
Martin Turner
Keyword(s):  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Receptor ◽  
Cross Linking ◽  
Marginal Zone B Cells ◽  
Survival Signal ◽  
B Cell Survival ◽  
Follicular B Cells ◽  
Deficient Mice

AbstractMice lacking all 3 Vav proteins fail to produce significant numbers of recirculating follicular or marginal zone B cells. Those B cells that do mature have shortened lifespans. The constitutive nuclear factor-kappaB (NF-κB) activity of resting naive B cells required Vav function and expression of cellular reticuloendotheliosis (c-Rel). Rel-A was reduced in Vav-deficient B cells. Furthermore, expression of the NF-κB-regulated antiapoptotic genes A1 and Bcl-2 was reduced in mature Vav-deficient B cells. Overexpression of Bcl-2 restored the number of mature follicular B cells in the spleens of Vav-deficient mice. When activated by B-cell receptor (BCR) cross-linking, Vav-deficient B cells failed to activate NF-κB. Vav proteins thus regulate an NF-κB-dependent survival signal in naive B cells and are required for NF-κB function after BCR cross-linking.

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.

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.

Sign in / Sign up

Export Citation Format

Share Document