scholarly journals Delta-Like-1 Changes the Immunomodulatory Property of OP9 Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-11
Author(s):  
Lei Zhang ◽  
Rui-Jie Dang ◽  
Yan-Mei Yang ◽  
Dian-Chao Cui ◽  
Ping Li ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
B Cell ◽  
Stromal Cells ◽  
B Lymphocyte ◽  
B Cell Development ◽  
T Cell Proliferation ◽  
No Production ◽  
Immunomodulatory Property

As stromal cells and recently confirmed mesenchymal stem cells, OP9 cells support hematopoiesis stem cell (HSC) differentiation into the B lymphocyte lineage, yet Delta-like-1 (DL1) overexpressing OP9 (OP9DL1) cells promote the development of early T lymphocytes from HSC. However, the immunomodulatory capacity of OP9 or OP9DL1 on mature B and T cell proliferation has not been elucidated. Here, we show that OP9 and OP9DL1 have similar proliferation capacities and immunophenotypes except DL1 expression. Compared with OP9, OP9DL1 displayed more osteogenesis and less adipogenesis when cultured in the respective induction media. Both OP9 and OP9DL1 inhibited mature B and T cell proliferation. Furthermore, OP9 showed stronger inhibition on B cell proliferation and OP9DL1 exhibited stronger inhibition on T cell proliferation. With stimulation, both OP9 and OP9DL1 showed increased nitrate oxide (NO) production. The NO levels of OP9 were higher than that of OP9DL1 when stimulated with TNFα/IFNγor LPS/IL4. Taken together, our study reveals a previously unrecognized role of OP9 and OP9DL1 in mature B and T cell proliferation. DL1 overexpression alone changed the properties of OP9 cells in addition to their role in early B cell development.

scholarly journals Engagement of the adhesion receptor CD22 triggers a potent stimulatory signal for B cells and blocking CD22/CD22L interactions impairs T-cell proliferation

Blood ◽  
1996 ◽  
Vol 87 (11) ◽  
pp. 4723-4730 ◽  
Author(s):  
J Tuscano ◽  
P Engel ◽  
TF Tedder ◽  
JH Kehrl
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
B Cell ◽  
B Lymphocyte ◽  
Tyrosine Phosphatase ◽  
Interleukin 2 ◽  
Culture Conditions ◽  
Cell Interactions ◽  
T Cell Proliferation ◽  
Downstream Signaling

The B-lymphocyte-restricted adhesion protein CD22 mediates sialic acid- dependent cell-cell interactions. Engagement of CD22 on B lymphocytes with a CD22 monoclonal antibody (MoAb) HB22.7 that blocks the binding of CD22 to its ligand(s) directly stimulated B-cell proliferation. In addition, the HB22.7 MoAb costimulated B-cell proliferation with either anti-IgM, interleukin-2 (IL-2), IL-4, or CD40 and triggered predominantly B-cell IgG secretion with IL-2. Even more striking levels of B-cell proliferation occurred with HB22.7 MoAb under culture conditions that enhanced B-B-cell interactions. In contrast, a nonblocking CD22 MoAb (CD22.5) poorly costimulated in similar experiments. The functional differences between the two antibodies likely result from differing abilities to trigger downstream signaling events as significant differences in CD22 tyrosine phosphorylation and the recruitment of the tyrosine kinase p53/56lyn and the tyrosine phosphatase SH-PTP1C were found. Besides their role in B-cell stimulation, CD22/CD22L interactions may also assist in regulating T- cell proliferation because inhibition of CD22-CD22L engagement with the HB22.7 MoAb impaired T-cell proliferation in a costimulatory assay. Thus, CD22/CD22L interactions result in stimulatory signals for both B and T lymphocytes.

scholarly journals Replication history of B lymphocytes reveals homeostatic proliferation and extensive antigen-induced B cell expansion

2007 ◽  
Vol 204 (3) ◽  
pp. 645-655 ◽  
Author(s):  
Menno C. van Zelm ◽  
Tomasz Szczepański ◽  
Mirjam van der Burg ◽  
Jacques J.M. van Dongen
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Expansion ◽  
B Lymphocyte ◽  
Somatic Hypermutation ◽  
Homeostatic Proliferation ◽  
History Of ◽  
Lymphocyte Homeostasis

The contribution of proliferation to B lymphocyte homeostasis and antigen responses is largely unknown. We quantified the replication history of mouse and human B lymphocyte subsets by calculating the ratio between genomic coding joints and signal joints on kappa-deleting recombination excision circles (KREC) of the IGK-deleting rearrangement. This approach was validated with in vitro proliferation studies. We demonstrate that naive mature B lymphocytes, but not transitional B lymphocytes, undergo in vivo homeostatic proliferation in the absence of somatic mutations in the periphery. T cell–dependent B cell proliferation was substantially higher and showed higher frequencies of somatic hypermutation than T cell–independent responses, fitting with the robustness and high affinity of T cell–dependent antibody responses. More extensive proliferation and somatic hypermutation in antigen-experienced B lymphocytes from human adults compared to children indicated consecutive responses upon additional antigen exposures. Our combined observations unravel the contribution of proliferation to both B lymphocyte homeostasis and antigen-induced B cell expansion. We propose an important role for both processes in humoral immunity. These new insights will support the understanding of peripheral B cell regeneration after hematopoietic stem cell transplantation or B cell–directed antibody therapy, and the identification of defects in homeostatic or antigen-induced B cell proliferation in patients with common variable immunodeficiency or another antibody deficiency.

scholarly journals Defective interleukin-2 production and responsiveness by T cells in patients with chronic lymphocytic leukemia of B cell variety

Blood ◽  
1986 ◽  
Vol 67 (2) ◽  
pp. 279-284 ◽  
Author(s):  
O Ayanlar-Batuman ◽  
E Ebert ◽  
SP Hauptman
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Proliferative Response ◽  
Interleukin 2 ◽  
Lymphocytic Leukemia ◽  
T Cell Proliferation ◽  
Activated T Cells

Abstract The present studies were designed to investigate the mechanism(s) of the defective T cell proliferative response to various stimuli in patients with B cell chronic lymphocytic leukemia B-CLL. In 14 patients with advanced B-CLL (stage III or IV) we found the T cell response in the autologous (auto) and allogeneic (allo) mixed lymphocyte reaction (MLR) to be 35.7% and 30% of the controls, respectively. Proliferation in the MLR depends upon the production of and response to interleukin 2 (IL 2), a T cell growth factor. IL 2 production in eight B-CLL patients was 22% of the control. The response to IL 2 was measured by the increase in the T cell proliferation in the MLR with the addition of IL 2. T cell proliferation in both the auto and allo MLR of CLL patients was significantly lower than in the controls after the addition of IL 2. The proliferative response of normal T cells to stimulation by CLL B cells was 50% of the control. This latter response was increased to control levels when cultures were supplemented with exogenous IL 2, suggesting that CLL B cells could stimulate IL 2 receptor generation in normal T cells in an allo MLR, but not IL 2 production. The presence of IL 2 receptors on activated T cells was directly determined using anti- Tac, a monoclonal antibody with specificity for the IL 2 receptor. Of the mitogen- or MLR-activated T cells in CLL patients, 6% and 10%, respectively, expressed Tac antigen, whereas identically stimulated control T cells were 60% and 47% Tac+, respectively. Our findings suggest that T cells in B-CLL are defective in their recognition of self or foreign major histocompatibility antigens as demonstrated by their impaired responsiveness in the MLR. Thus, these cells are unable to produce IL 2 or generate IL 2 receptors.

scholarly journals Suppression of T-cell proliferation by Mycobacterium leprae and its products: the role of lipopolysaccharide.

1990 ◽  
Vol 87 (3) ◽  
pp. 973-977 ◽  
Author(s):  
A. Molloy ◽  
G. Gaudernack ◽  
W. R. Levis ◽  
Z. A. Cohn ◽  
G. Kaplan
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Mycobacterium Leprae ◽  
T Cell Proliferation

scholarly journals Immunosuppressive role of semaphorin-3A on T cell proliferation is mediated by inhibition of actin cytoskeleton reorganization

2006 ◽  
Vol 36 (7) ◽  
pp. 1782-1793 ◽  
Author(s):  
Yves Lepelletier ◽  
Ivan Cruz Moura ◽  
Réda Hadj-Slimane ◽  
Amédée Renand ◽  
Susana Fiorentino ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Actin Cytoskeleton ◽  
T Cell Proliferation ◽  
Semaphorin 3A ◽  
Cytoskeleton Reorganization

IL-7 Effects on Thymocyte Progenitors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3318-3318
Author(s):  
Nahed El Kassar ◽  
Baishakhi Choudhury ◽  
Francis Flomerfelt ◽  
Philip J. Lucas ◽  
Veena Kapoor ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
B Cell ◽  
Notch Signaling ◽  
Stromal Cells ◽  
T Cell Development ◽  
Fold Increase ◽  
Cell Development ◽  
B Cell Development ◽  
Over Expression

Abstract IL-7 is a non-redundant cytokine in T cell development. We studied the role of IL-7 in early T-cell development using a model of transgenic (Tg) mice with the murine IL-7 gene under control of the lck proximal promoter. At high IL-7 over-expression (x39 fold increase at day 1 in total thymic tissue), we observed a disruption of TCRαβ development along with increased B cell development in the thymus (7- to 13-fold increase) (El Kassar, Blood, 2004). In order to further explore abnormal T and B cell thymic development in these mice, we first confirmed that they both arise in parallel and were non-cell autonomous, by in vivo injection of neutralizing anti-IL-7 MAb and mixed bone marrow chimera experiments. Using a six color flow cytometry analysis, we found a dramatic decrease of the early thymocyte progenitors (ETPs, lin−CD44+CD25−c-kithiIL-7R−/lo) in the adult Tg mice (x4.7 fold decrease). Lin−CD44+CD25−c-kit+ thymocytes were sorted and cultured on OP9 and OP9 delta-like1 (OP9-DL1) stromal cells (kindly provided by Pr Zuniga Pflucker). At day 14, we observed an important decrease of T cell development (54% vs. 1% of DP cells) and an increase of NK cells (x5 fold increase) in the Tg-derived DN1 cell culture. DN2 (Lin−CD44+CD25−c-kit+) Tg thymocytes showed the same, but less dramatic abnormalities. While DN1 progenitors developed effectively into B220+CD19+ cells on OP9 stromal cells, no B cell development was observed on OP-DL stromal cells from DN1-Tg derived progenitors or by addition of increasingly high doses of IL-7 (x10, x40, x160) to normal B6-derived DN1 progenitors. Instead, a block of T-cell development was observed with increased IL-7. We hypothesized a down regulation of Notch signaling by IL-7 over-expression and analyzed by FACS Notch expression in the DN thymocytes. By staining the intra-cellular part of Notch cleaved after Notch 1/Notch ligand activation, Tg-derived DN2 cells showed decreased Notch signaling. More importantly, HES expression was decreased in the DN2, DN3 and DN4 fractions by semi-quantitative PCR. Sorted Pro/Pre B cells from Tg thymi showed TCR Dβ1-Jβ1 rearrangement indicating their T specific origin, in opposition to Pro/Pre B cells sorted from the bone marrow of the same mice. We suggest that more than one immature progenitor seeds the thymus from the bone marrow. While ETPs had T and NK proliferative capacity, another thymic progenitor with B potential may be responsible for thymic B cell development in normal and IL-7 Tg mice. Finally, IL-7 over-expression may induce a decreased Notch signaling in thymic progenitors, inducing a switch of T vs. B lineage development.

CD11b+gr-1+ myeloid Derived Suppressor Cells (MDSC) In Normal Bone Marrow Suppress T Cell Proliferation and Enhance T-Regulatory Function Via a IL10-, IL4- and IDO-Independent Mechanism

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4801-4801 ◽  
Author(s):  
Parvin Forghani ◽  
Wayne Harris ◽  
jian-Ming Li ◽  
M.R. Khorramizadeh ◽  
Edmund Waller
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Regulatory Function ◽  
T Cell Proliferation ◽  
Suppressive Activity ◽  
Ifn Γ

Abstract Abstract 4801 MDSC have been described as an important negative regulators of autologous anti-cancer immune responses. Considering the important role of MDSC in immune regulation in allogenic stem cell and organ transplantation, we undertook an investigation of the mechanism(s) by which MDSC inhibit T–cell activation and proliferation, and tested the hypothesis that local cytokine secretion or IDO activity is required for suppression of T-cell proliferation. Two separate populations CD11bhiGr-1hi and CD11bhi Gr-1int were isolated by high-speed FACS from lineage- BM antigen presenting cells (C57 & BALB/c mice). Both MDSC subsets had potent capacity for in–vitro suppression of CD4+ and CD8+ T cells proliferation in response to anti-CD3/anti-CD28 beads and Con A. A ratio of 0.5/1 MDSC: T-cells were sufficient to inhibit >66% control levels of T-cell proliferation. MDSC isolated from transgenic mice that had been “knocked-out” for IFN-γ and IDO had equivalent suppressive activity as MDSC from wild-type donors. Addition of saturating concentrations of anti IL-10 and IL-4 MAb, or in combination with anti- IFN-γ MAb did not abrogate MDSC-suppressive activity. Ex-vivo culture of MDSC with mitogen-activated T-cells generated two—fold more Fox-p3 T-reg compared with cultures of T cell plus mitogen. Data will be presented regarding the novel role of MDSC involving in the homeostasis regulation of normal T-cell activation and proliferation in non-tumor-bearing mice. Disclosures: No relevant conflicts of interest to declare.

Pak2 Regulates MDSC Development and Function

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 705-705
Author(s):  
Yi Zeng ◽  
Seongmin Hahn ◽  
Jessica Stokes ◽  
Emely Hoffman ◽  
Jonathan Chernoff ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Progenitor Cells ◽  
Lineage Commitment ◽  
T Cell Proliferation ◽  
Myeloid Lineage ◽  
Suppressive Function ◽  
Gm Csf ◽  
Group I

Abstract Myeloid derived suppressor cells (MDSCs) are a heterogeneous cell population at various stages of differentiation that can increase under various pathologic conditions such as cancer, infection or inflammation, displaying suppressive function. It is well recognized that MDSCs contribute to tumor evasion by suppressing cell-mediated immunity. Based on the differential expression of Ly6C and/or Ly6G in mice, MDSCs are characterized as granulocytic (CD11b+Ly6G+Ly6Clow) or monocytic MDSCs (CD11b+Ly6Glow/−Ly6Chi). These subsets induce T-cell hyporesponsiveness and can have various functions and distribution depending on their environment. Although much research has focused on the tumorigenic effects of MDSCs, studies on the regulation of their development during hematopoiesis remain limited. p21-activated kinases (Paks) are serine/threonine kinases that regulate diverse cellular activities including cytoskeletal remodeling, cell motility, proliferation, apoptosis and mitosis. Despite active research on pharmacological inhibition of group I Paks in treating solid tumors, few studies have examined the role of Paks in modulating normal hematopoiesis. Knowledge of the role of Pak2 in regulating long-term hematopoiesis and lineage commitment remains limited. Utilizing a conditional Pak2-KO murine model, we have previously demonstrated that Pak2 disruption in hematopoietic stem/progenitor cells (HSPCs) induces myeloid lineage skewing and CD11b+Gr1+ cell expansion in mice. Compared to mice reconstituted with wild type (WT) bone marrow (BM), mice transplanted with Pak2-KO BM displayed a significantly higher percentage of granulocyte-monocyte progenitors (GMPs) in the BM and higher numbers of CD11b+Gr1+ cells in the spleen. In this study, we demonstrated that CD11b+Gr1high cells isolated from the spleens of mice with Pak2-KO BM displayed significantly greater suppressive function on T cell proliferation in vitro, consistent with MDSC phenotype. There was a near 2-fold increase in the numbers of both granulocytic and monocytic splenic MDSCs in mice reconstituted with Pak2-KO BM. At HSPC level, Pak2-KO BM yielded greater than 3-fold more colonies in response to GM-CSF but not G-CSF or M-CSF when compared to WT cells, indicating selective hypersensitivity to GM-CSF. In parallel experiments, Pak2-KO and WT BM C-kit+ cells that were enriched for hematopoietic progenitor cells (HPCs) were cultured in liquid culture in the presence of GM-CSF. Pak2-KO BM C-kit+ cells yielded greater than 2-fold higher numbers of CD11b+Gr1+ MDSCs that displayed potent suppression on CD8+ T cell proliferation. These data demonstrate that Pak2 disruption increases HPC sensitivity to GM-CSF signaling and drives lineage commitment toward granulocyte-monocyte lineage thus promoting MDSC development. In addition, we have also found that Pak2 deficient MDSCs are more proliferative and more resistant to apoptosis when compared to WT CD11b+Gr1+cells, thus contributing to expansion of this population in vivo. Loss of Pak2 decreases MDSC sensitivity to apoptosis through differential regulation of multiple pro- and anti-apoptotic gene expression. Furthermore, Pak2 disruption down regulates the expression of IRF8, a well-described myeloid transcription factor. Together, our data indicate that loss of Pak2 promotes HPC myeloid lineage commitment and CD11b+Gr1+ MDSC proliferation while suppressing apoptotic cell death in these cells. Further studies are ongoing to determine the interaction between Pak2 and IRF8. Disclosures No relevant conflicts of interest to declare.

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