scholarly journals Aberrant Regulation of Hematopoiesis by T Cells in BAZF-Deficient Mice

2007 ◽  
Vol 27 (15) ◽  
pp. 5275-5285 ◽  
Author(s):  
Hal E. Broxmeyer ◽  
Sarita Sehra ◽  
Scott Cooper ◽  
Lisa M. Toney ◽  
Saritha Kusam ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Physiological Role ◽  
Normal Function ◽  
Wild Type ◽  
Indirect Pathway ◽  
Hematopoietic Progenitor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Deficient Mice

ABSTRACTThe BAZF (BCL-6b) protein is highly similar to the BCL-6 transcriptional repressor. While BCL-6 has been characterized extensively, relatively little is known about the normal function of BAZF. In order to understand the physiological role of BAZF, we created BAZF-deficient mice. Unlike BCL-6-deficient mice, BAZF-deficient mice are healthy and normal in size. However, BAZF-deficient mice have a hematopoietic progenitor phenotype that is almost identical to that of BCL-6-deficient mice. Compared to wild-type mice, both BAZF-deficient and BCL-6-deficient mice have greatly reduced numbers of cycling hematopoietic progenitor cells (HPC) in the BM and greatly increased numbers of cycling HPC in the spleen. In contrast to HPC from wild-type mice, HPC from BAZF-deficient and BCL-6-deficient mice are resistant to chemokine-induced myelosuppression and do not show a synergistic growth response to granulocyte-macrophage colony-stimulating factor plus stem cell factor. Depletion of CD8 T cells in BAZF-deficient mice reverses several of the hematopoietic defects in these mice. Since both BAZF- and BCL-6-deficient mice have defects in CD8 T-cell differentiation, we hypothesize that both BCL-6 and BAZF regulate HPC homeostasis by an indirect pathway involving CD8 T cells.

scholarly journals Induction of Dendritic Cell Differentiation by Granulocyte-Macrophage Colony-Stimulating Factor, Stem Cell Factor, and Tumor Necrosis Factor α In Vitro From Lineage Phenotypes-Negative c-kit+ Murine Hematopoietic Progenitor Cells

Blood ◽  
1997 ◽  
Vol 90 (12) ◽  
pp. 4842-4853 ◽  
Author(s):  
Yi Zhang ◽  
Naofumi Mukaida ◽  
Jian-bin Wang ◽  
Akihisa Harada ◽  
Mariko Akiyama ◽  
...  
Keyword(s):  
Stem Cell Factor ◽  
Wild Type Mouse ◽  
Wild Type ◽  
Hematopoietic Progenitor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Deficient Mice ◽  
Necrosis Factor

To elucidate the capacity of murine early hematopoietic progenitor cells (HPCs) to differentiate into dendritic cells (DCs), lineage phenotypes (Lin)−c-kit+ HPCs were highly purified from either wild-type or tumor necrosis factor (TNF) receptor p55 (TNF-Rp55)-deficient mice. Upon culture with granulocyte-macrophage colony-stimulating factor (GM-CSF) and stem cell factor (SCF) for 14 days, wild-type mouse Lin−c-kit+ HPCs did not exhibit characteristic features of DC such as sheet-like projections and veil processes. Moreover, these cells expressed a marginal level of DC markers such as DEC-205, CD86, and barely supported allogenic MLR. However, the addition of mouse TNFα generated a large number of cells with typical DC morphology, expression of high levels of Ia, DEC-205, CD86, and function of stimulating allogenic MLR. Moreover, a proportion of these mature DCs and thymic DCs expressed Thy-1 mRNA as well as Thy-1 antigen, whereas freshly isolated splenic DCs did not. These results suggested that DCs generated in our culture system phenotypically resemble thymic ones. In contrast, mouse TNFα failed to induce TNF-Rp55-deficient mice-derived Lin−c-kit+ HPCs to generate DCs with characteristic morphology, immunophenotype, and accessory function for T cells under the same culture conditions, suggesting a crucial role of TNF-Rp55 in TNFα-mediated DC differentiation from HPCs. Interestingly, human TNFα, which can bind to mouse TNF-Rp55 but not TNF-Rp75, was incapable to augment DC generation from wild-type mouse Lin−c-kit+ HPCs. Collectively, these results suggest that TNFα has a pivotal role in DC generation from murine early HPCs in collaboration with GM-CSF and SCF through the interaction of TNF-Rp55 and TNF-Rp75.

scholarly journals Induction of Dendritic Cell Differentiation by Granulocyte-Macrophage Colony-Stimulating Factor, Stem Cell Factor, and Tumor Necrosis Factor α In Vitro From Lineage Phenotypes-Negative c-kit+ Murine Hematopoietic Progenitor Cells

Blood ◽  
1997 ◽  
Vol 90 (12) ◽  
pp. 4842-4853 ◽  
Author(s):  
Yi Zhang ◽  
Naofumi Mukaida ◽  
Jian-bin Wang ◽  
Akihisa Harada ◽  
Mariko Akiyama ◽  
...  
Keyword(s):  
Stem Cell Factor ◽  
Wild Type Mouse ◽  
Wild Type ◽  
Hematopoietic Progenitor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Deficient Mice ◽  
Necrosis Factor

Abstract To elucidate the capacity of murine early hematopoietic progenitor cells (HPCs) to differentiate into dendritic cells (DCs), lineage phenotypes (Lin)−c-kit+ HPCs were highly purified from either wild-type or tumor necrosis factor (TNF) receptor p55 (TNF-Rp55)-deficient mice. Upon culture with granulocyte-macrophage colony-stimulating factor (GM-CSF) and stem cell factor (SCF) for 14 days, wild-type mouse Lin−c-kit+ HPCs did not exhibit characteristic features of DC such as sheet-like projections and veil processes. Moreover, these cells expressed a marginal level of DC markers such as DEC-205, CD86, and barely supported allogenic MLR. However, the addition of mouse TNFα generated a large number of cells with typical DC morphology, expression of high levels of Ia, DEC-205, CD86, and function of stimulating allogenic MLR. Moreover, a proportion of these mature DCs and thymic DCs expressed Thy-1 mRNA as well as Thy-1 antigen, whereas freshly isolated splenic DCs did not. These results suggested that DCs generated in our culture system phenotypically resemble thymic ones. In contrast, mouse TNFα failed to induce TNF-Rp55-deficient mice-derived Lin−c-kit+ HPCs to generate DCs with characteristic morphology, immunophenotype, and accessory function for T cells under the same culture conditions, suggesting a crucial role of TNF-Rp55 in TNFα-mediated DC differentiation from HPCs. Interestingly, human TNFα, which can bind to mouse TNF-Rp55 but not TNF-Rp75, was incapable to augment DC generation from wild-type mouse Lin−c-kit+ HPCs. Collectively, these results suggest that TNFα has a pivotal role in DC generation from murine early HPCs in collaboration with GM-CSF and SCF through the interaction of TNF-Rp55 and TNF-Rp75.

CCR5 deficiency decreases susceptibility to experimental cerebral malaria

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4253-4259 ◽  
Author(s):  
Elodie Belnoue ◽  
Michèle Kayibanda ◽  
Jean-Christophe Deschemin ◽  
Mireille Viguier ◽  
Matthias Mack ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Cd8 T Cells ◽  
Cytokine Production ◽  
Wild Type ◽  
Experimental Cerebral Malaria ◽  
Pathologic Features ◽  
Th1 Cytokine ◽  
The Brain ◽  
Deficient Mice

Abstract Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8+ T-cell subset of these brain-sequestered leukocytes is critical for progression to CM. Chemokine receptor–5 (CCR5) is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70% to 85% of wild-type and CCR5+/- mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurologic signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5+ leukocytes, particularly CCR5+ CD8+ T cells, as well as increases in T-helper 1 (Th1) cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8+ T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM)–chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5+ BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM.

scholarly journals CD8 T Cells Require Gamma Interferon To Clear Borna Disease Virus from the Brain and Prevent Immune System-Mediated Neuronal Damage

2005 ◽  
Vol 79 (21) ◽  
pp. 13509-13518 ◽  
Author(s):  
Jürgen Hausmann ◽  
Axel Pagenstecher ◽  
Karen Baur ◽  
Kirsten Richter ◽  
Hanns-Joachim Rziha ◽  
...  
Keyword(s):  
T Cells ◽  
Disease Virus ◽  
Cd8 T Cells ◽  
Gamma Interferon ◽  
Wild Type ◽  
Borna Disease Virus ◽  
Ifn Γ ◽  
The Brain ◽  
Deficient Mice ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV) frequently causes meningoencephalitis and fatal neurological disease in young but not old mice of strain MRL. Disease does not result from the virus-induced destruction of infected neurons. Rather, it is mediated by H-2 k -restricted antiviral CD8 T cells that recognize a peptide derived from the BDV nucleoprotein N. Persistent BDV infection in mice is not spontaneously cleared. We report here that N-specific vaccination can protect wild-type MRL mice but not mutant MRL mice lacking gamma interferon (IFN-γ) from persistent infection with BDV. Furthermore, we observed a significant degree of resistance of old MRL mice to persistent BDV infection that depended on the presence of CD8 T cells. We found that virus initially infected hippocampal neurons around 2 weeks after intracerebral infection but was eventually cleared in most wild-type MRL mice. Unexpectedly, young as well as old IFN-γ-deficient MRL mice were completely susceptible to infection with BDV. Moreover, neurons in the CA1 region of the hippocampus were severely damaged in most diseased IFN-γ-deficient mice but not in wild-type mice. Furthermore, large numbers of eosinophils were present in the inflamed brains of IFN-γ-deficient mice but not in those of wild-type mice, presumably because of increased intracerebral synthesis of interleukin-13 and the chemokines CCL1 and CCL11, which can attract eosinophils. These results demonstrate that IFN-γ plays a central role in host resistance against infection of the central nervous system with BDV and in clearance of BDV from neurons. They further indicate that IFN-γ may function as a neuroprotective factor that can limit the loss of neurons in the course of antiviral immune responses in the brain.

Dendritic cells generated in the presence of granulocyte-macrophage colony-stimulating factor and IFN-α are potent inducers of HIV-specific CD8 T cells

AIDS ◽  
2003 ◽  
Vol 17 (12) ◽  
pp. 1731-1740 ◽  
Author(s):  
Cédric Carbonneil ◽  
Albertine Aouba ◽  
Marianne Burgard ◽  
Sylvain Cardinaud ◽  
Christine Rouzioux ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd8 T Cells ◽  
Colony Stimulating Factor ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

scholarly journals Tumor vaccination with macrophage colony-stimulating factor-producing Lewis lung carcinoma in mice

Blood ◽  
1996 ◽  
Vol 88 (3) ◽  
pp. 955-961
Author(s):  
T Morita ◽  
K Ikeda ◽  
M Douzono ◽  
M Yamada ◽  
F Kimura ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Lewis Lung Carcinoma ◽  
Lewis Lung ◽  
Colony Stimulating Factor ◽  
Wild Type ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Expression of various cytokines by cytokine gene-transduced tumor cells has been shown to increase antitumor immunity of tumor-bearing hosts. In the present study, macrophage-colony stimulating factor (M-CSF) cDNA was retrovirally transfected into Lewis lung carcinoma cells (3LL) of C57BL/6 mouse origin, and the effects of M-CSF expression were studied by inoculating syngeneic C57BL/6 mice with M-CSF-expressing 3LL cells. The mice inoculated with the lowest M-CSF-producing 3LL clone showed significant prolongation of the survival compared with wild-type 3LL- Inoculated mice, and 70% or more of the mice inoculated with 3LL clones with higher M-CSF production rejected inoculation. Mice injected with radiation-inactivated M-CSF-expressing 3LL cells before or after Inoculation of wild-type 3LL cells showed prolonged survival compared with mice injected with radiated control 3LL cells before or after transplantation of wild-type cells. In vivo depletion of effector subpopulations by injection of antibodies against CD4+ T cells, CD8+ T cells, or natural killer (NK) cells suggested involvement of NK cells and CD4+ T cells in M-CSF-mediated antitumor cytotoxicity in M-CSF- producing 3LL cells-inoculated mice. Severe combined immunodeficiency (SCID) mice with defective T- and B-cell function showed prolonged survival duration after inoculation with M-CSF-expressing 3LL cells compared with those transplanted with control 3LL cells, and this effect of M-CSF expression by 3LL-cells in SCID mice was also abolished by in vivo depletion of NK cells by antibody injection. These findings together with the previous reports that M-CSF augments antibody- dependent and-independent antitumor cytotoxicity suggest that M-CSF induces tumor immunity in this cytokine-expressing tumor- transplantation model.

scholarly journals Jak3 Selectively Regulates Bax and Bcl-2 Expression To Promote T-Cell Development

2001 ◽  
Vol 21 (2) ◽  
pp. 678-689 ◽  
Author(s):  
Renren Wen ◽  
Demin Wang ◽  
Catriona McKay ◽  
Kevin D. Bunting ◽  
Jean-Christophe Marine ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Development ◽  
Cell Development ◽  
Lymphoid Cells ◽  
Wild Type ◽  
Cell Numbers ◽  
Deficient Mice ◽  
T Lymphopoiesis

ABSTRACT Jak3-deficient mice display vastly reduced numbers of lymphoid cells. Thymocytes and peripheral T cells from Jak3-deficient mice have a high apoptotic index, suggesting that Jak3 provides survival signals. Here we report that Jak3 regulates T lymphopoiesis at least in part through its selective regulation of Bax and Bcl-2. Jak3-deficient thymocytes express elevated levels of Bax and reduced levels of Bcl-2 relative to those in wild-type littermates. Notably, up-regulation of Bax in Jak3-deficient T cells is physiologically relevant, as Jak3 Bax double-null mice have marked increases in thymocyte and peripheral T-cell numbers. Rescue of T lymphopoiesis by Bax loss was selective, as mice deficient in Jak3 plus p53 or in Jak3 plus Fas remained lymphopenic. However, Bax loss failed to restore proper ratios of peripheral CD4/CD8 T cells, which are abnormally high in Jak3-null mice. Transplantation into Jak3-deficient mice of Jak3-null bone marrow transduced with a Bcl-2-expressing retrovirus also improved peripheral T-cell numbers and restored the ratio of peripheral CD4/CD8 T cells to wild-type levels. The data support the concepts that Jak kinases regulate cell survival through their selective and cell context-dependent regulation of pro- and antiapoptotic Bcl-2 family proteins and that Bax and Bcl-2 play distinct roles in T-cell development.

scholarly journals H2-M3–restricted CD8+ T cells are not required for MHC class Ib–restricted immunity against Listeria monocytogenes

2006 ◽  
Vol 203 (2) ◽  
pp. 383-391 ◽  
Author(s):  
Sarah E.F. D'Orazio ◽  
Christine A. Shaw ◽  
Michael N. Starnbach
Keyword(s):  
T Cells ◽  
Listeria Monocytogenes ◽  
Cd8 T Cells ◽  
T Cell Response ◽  
Mhc Class Ib ◽  
Wild Type ◽  
Histocompatibility Complex ◽  
Mutant Strains ◽  
Antigen Presenting ◽  
Deficient Mice

Studies using major histocompatibility complex (MHC)-Ia–deficient mice have shown that MHC-Ib–restricted CD8+ T cells can clear infections caused by intracellular pathogens such as Listeria monocytogenes. M3-restricted CD8+ T cells, which recognize short hydrophobic N-formylated peptides, appear to comprise a substantial portion of the MHC-Ib–restricted T cell response in the mouse model of L. monocytogenes infection. In this study, we isolated formyltransferase (fmt) mutant strains of L. monocytogenes that lacked the ability to add formyl groups to nascent polypeptides. These fmt mutant Listeria strains did not produce antigens that could be recognized by M3-restricted T cells. We showed that immunization of MHC-Ia–deficient mice with fmt mutant Listeria resulted in stimulation of a protective memory response that cleared subsequent challenge with wild-type L. monocytogenes, despite the fact that M3-restricted CD8+ T cells did not proliferate in these mice. These data suggest that M3-restricted T cells are not required for protection against L. monocytogenes and underscore the importance of searching for new antigen-presenting molecules among the large MHC-Ib family of proteins.

ROLE OF CD8+ T CELLS IN CARDIAC ALLOGRAFT REJECTION IN WILD-TYPE AND CD28-DEFICIENT MICE.

2000 ◽  
Vol 69 (Supplement) ◽  
pp. S413 ◽  
Author(s):  
Gregory L. Szot ◽  
Ping Zhou ◽  
Jun Wang ◽  
Zhong Guo ◽  
Kenneth A. Newell ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Allograft Rejection ◽  
Cardiac Allograft ◽  
Wild Type ◽  
Cardiac Allograft Rejection ◽  
Deficient Mice

scholarly journals Gab3-Deficient Mice Exhibit Normal Development and Hematopoiesis and Are Immunocompetent

2003 ◽  
Vol 23 (7) ◽  
pp. 2415-2424 ◽  
Author(s):  
Martina Seiffert ◽  
Joseph M. Custodio ◽  
Ingrid Wolf ◽  
Michael Harkey ◽  
Yan Liu ◽  
...  
Keyword(s):  
B Lymphocyte ◽  
Physiological Role ◽  
Normal Function ◽  
Antigen Receptors ◽  
Normal Numbers ◽  
Protein Antigens ◽  
Mouse Development ◽  
Macrophage Differentiation ◽  
Macrophage Colony ◽  
Deficient Mice

ABSTRACT Gab proteins are intracellular scaffolding and docking molecules involved in signaling pathways mediated by various growth factor, cytokine, or antigen receptors. Gab3 has been shown to act downstream of the macrophage colony-stimulating factor receptor, c-Fms, and to be important for macrophage differentiation. To analyze the physiological role of Gab3, we used homologous recombination to generate mice deficient in Gab3. Gab3−/− mice develop normally, are visually indistinguishable from their wild-type littermates, and are healthy and fertile. To obtain a detailed expression pattern of Gab3, we generated Gab3-specific monoclonal antibodies. Immunoblotting revealed a predominant expression of Gab3 in lymphocytes and bone marrow-derived macrophages. However, detailed analysis demonstrated that hematopoiesis in mice lacking Gab3 is not impaired and that macrophages develop in normal numbers and exhibit normal function. The lack of Gab3 expression during macrophage differentiation is not compensated for by increased levels of Gab1 or Gab2 mRNA. Furthermore, Gab3-deficient mice have no major immune deficiency in T- and B-lymphocyte responses to protein antigens or during viral infection. In addition, allergic responses in Gab3-deficient mice appeared to be normal. Together, these data demonstrate that loss of Gab3 does not result in detectable defects in normal mouse development, hematopoiesis, or immune system function.

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