scholarly journals Inhibition of T Cell and Stimulation of B Cell Proliferation by Restraint Stress Mediated by Voltage-Gated Potassium Channel 1.3 Expression

2015 ◽  
Vol 05 (03) ◽  
pp. 94-104 ◽  
Author(s):  
Juan Feng ◽  
Shiqiang Wang ◽  
Demao Song
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Potassium Channel ◽  
B Cell ◽  
Restraint Stress ◽  
Voltage Gated ◽  
Stimulation Of

Chronic Lymphocytic Leukemia Cells Exhibit Inhibitory Properties of Regulatory B Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3874-3874
Author(s):  
Shimrit Ringelstein-Harlev ◽  
Irit Avivi ◽  
Lina Bisharat ◽  
Tamar Katz
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Fold Increase ◽  
Lymphocytic Leukemia ◽  
T Cell Proliferation ◽  
Cell Contact ◽  
Stimulation Of

Abstract Abstract 3874 Background: Chronic lymphocytic leukemia (CLL) is a mature B-cell malignancy, characterized by distinct immune suppression rendering both tumor cells and invading pathogens invisible to the immune system. However, CLL cells also display profound immune sensitivity as proven by long-term remissions achieved with allogeneic bone marrow transplantation. Many phenotypic properties of B-CLL cells resemble a subset of B-cells, studied mostly in autoimmunity and termed regulatory B cells (Bregs). Bregs are thought to suppress CD4+ T-cell mediated immune responses, directly through cell contact and indirectly through inhibitory cytokines. This study aims to define whether malignant B-CLL cells exhibit Breg suppressive properties, contributing to immune dysfunction in this disease. Methods: B-cells were isolated from peripheral blood mononuclear cells (PBMCs) of untreated CLL patients (Rai stages 0-IV) using immunomagnetic separation (STEMCELL technologies). Naïve cells and those stimulated with B-cell activators TLR-9 agonist or CD40Ligand (CD40L) were analyzed by FACS for Breg phenotypic markers and intracellular IL-10. Additionally, B-CLL cell effects on autologous CD4+ T cells (isolated by immunomagnetic beads; Miltenyi Biotec) were studied. T-cells were stimulated with anti-CD3/CD28 antibodies and IL-2, and exposed to B-cells either directly or through hanging cell culture inserts (Millipore) preventing physical cell-cell contact. T-cell proliferation was assessed using the carboxyfluorescein diacetate succinimidyl ester (CFSE) method and phenotype was analyzed by FACS. Results: B-cell phenotype was studied in 11 patients. Breg markers (CD5, CD38, CD25 and intracellular IL-10) as well as inhibitory molecules PD-1 and PDL-1 were expressed at high levels on B-CLL cells (62%, 37%, 50%, 52%, 29%, 61%, respectively), although not every patient expressed all markers. These expression levels were higher than those reported for normal peripheral blood B-cells. TLR-9 stimulation of B-CLL cells resulted in a 5.7-fold increase in expression of CD25 in 77% of patients. Increments were also observed in IL-10 (1.9-fold; 62% of patients), PDL-1 (1.96-fold; 83% of patients) and PD-1 (2.19-fold; 57% of patients). Of 13 patients whose T-cell proliferation potential was evaluated after exposure to B-CLL cells, proliferation was induced in only 69%; in the other 31% (4 patients) no proliferation was observed; moreover, inhibition was demonstrated in one of them. Among the former group only 33% of patients expressed CD25 on their B-cells, whereas within the latter group, 75% of patients' B-cells were CD25-positive. Stimulation of B-CLL cells with TLR-9 markedly increased their inhibitory capacity (72% of 11 patients tested), while CD40L stimulation caused a weaker effect (50% of 6 patients tested). T-cell proliferation remained unchanged when evaluated using a Transwell system versus a contact system, as demonstrated in 3 of 4 experiments. T-cells exposed to B-CLL cells altered the ratio of CD25high vs. CD25low T-cells in favor of CD25 high cells (2.44-fold increase for stimulation with naïve B-CLL cells, 4.94-fold increase with TLR-9 stimulated cells; in all the 5 tested patients). Conclusions: Previously identified Breg markers as well as PD-1 and PDL-1 were highly expressed in B-CLL cells, supporting the role of these cells in shaping an immune tolerant environment, enabling tumor growth. Stimulation of B-CLL cells with TLR-9 agonist enhanced this phenotype and resulted in consistent inhibition of T-cell proliferation, likely to be independent of cell-to-cell contact. These findings demonstrate the presence of Breg features within the CLL clone. The observed alterations in CD4+CD25+ T-cell populations after exposure to B-CLL cells suggest induction of T-regulatory cells, another mechanism supposedly used by Bregs for immune suppression. The enhancement of Breg properties in B-CLL cells following B-cell activation can serve as a platform for further studies of the innate regulatory mechanisms utilized by tumor cells. Disclosures: No relevant conflicts of interest to declare.

T-cell control of B-cell proliferation uncoupled from differentiation

1982 ◽  
Vol 74 (2) ◽  
pp. 269-276 ◽  
Author(s):  
Andrew Yen ◽  
David G. Fairchild
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
B Cell ◽  
Cell Control

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 Inhibition of normal B-cell function by human immunodeficiency virus envelope glycoprotein, gp120

Blood ◽  
1992 ◽  
Vol 79 (5) ◽  
pp. 1245-1254 ◽  
Author(s):  
N Chirmule ◽  
N Oyaizu ◽  
VS Kalyanaraman ◽  
S Pahwa
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Function ◽  
Cell Contact ◽  
Cell Proliferation And Differentiation ◽  
Cell Clones ◽  
Glycoprotein Gp120

Abstract Despite the occurrence of hypergammaglobulinemia in human immunodeficiency virus (HIV) infection, specific antibody production and in vitro B-cell differentiation responses are frequently impaired. In this study, we have examined the effects of HIV envelope glycoprotein gp120 on T-helper cell function for B cells. In the culture system used, B-cell functional responses were dependent on T-B- cell contact, since separation of T and B cells in double chambers by Transwell membranes rendered the B cells unresponsive in assays of antigen-induced B-cell proliferation and differentiation. Cytokines secreted by T cells were also essential, since anti-CD3 monoclonal antibody (mAb)-activated, paraformaldehyde-fixed T-cell clones failed to induce B-cell proliferation and differentiation. Pretreatment of the CD4+ antigen-specific T cells with gp120 was found to impair their ability to help autologous B cells, as determined by B-cell proliferation, polyclonal IgG secretion, and antigen-specific IgG secretion. The gp120-induced inhibition was specific in that it was blocked by soluble CD4. Furthermore, only fractionated small B cells (which are T-cell-dependent in their function) manifested impaired responses when cultured with gp120-treated T cells. Antigen-induced interleukin (IL)-2 and IL-4, but not IL-6, secretion were markedly reduced in gp120-treated T-cell clones. Addition of exogenous cytokines failed to compensate for defective helper function of gp120-treated T cells. The findings in this study indicate that gp120 impairs helper functions of CD4+ T cells by interfering with T-B-cell contact- dependent interaction; the inhibitory effects of soluble envelope proteins of HIV may contribute to the immunopathogenesis of the HIV- associated disease manifestations.

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.

CD40-Activated B-Cell Chronic Lymphocytic Leukemia Cells for Tumor Immunotherapy: Stimulation of Allogeneic Versus Autologous T Cells Generates Different Types of Effector Cells

Blood ◽  
1999 ◽  
Vol 93 (6) ◽  
pp. 1992-2002 ◽  
Author(s):  
Raymund Buhmann ◽  
Annette Nolte ◽  
Doreen Westhaus ◽  
Bertold Emmerich ◽  
Michael Hallek
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Tumor Antigens ◽  
Lymphocytic Leukemia ◽  
T Cell Anergy ◽  
Cell Anergy ◽  
Cell Chronic Lymphocytic Leukemia ◽  
Stimulation Of

Although spontaneous remissions may rarely occur in B-cell chronic lymphocytic leukemia (B-CLL), T cells do generally not develop a clinically significant response against B-CLL cells. Because this T-cell anergy against B-CLL cells may be caused by the inability of B-CLL cells to present tumor-antigens efficiently, we examined the possibility of upregulating critical costimulatory (B7-1 and B7-2) and adhesion molecules (ICAM-1 and LFA-3) on B-CLL cells to improve antigen presentation. The stimulation of B-CLL cells via CD40 by culture on CD40L expressing feeder cells induced a strong upregulation of costimulatory and adhesion molecules and turned the B-CLL cells into efficient antigen-presenting cells (APCs). CD40-activated B-CLL (CD40-CLL) cells stimulated the proliferation of both CD4+ and CD8+ T cells. Interestingly, stimulation of allogeneic versus autologous T cells resulted in the expansion of different effector populations. Allogeneic CD40-CLL cells allowed for the expansion of specific CD8+cytolytic T cells (CTL). In marked contrast, autologous CD40-CLL cells did not induce a relevant CTL response, but rather stimulated a CD4+, Th1-like T-cell population that expressed high levels of CD40L and released interferon-γ in response to stimulation by CD40-CLL cells. Together, these results support the view that CD40 activation of B-CLL cells might reverse T-cell anergy against the neoplastic cell clone, although the character of the immune response depends on the major histocompatibility complex (MHC) background on which the CLL or tumor antigens are presented. These findings may have important implications for the design of cellular immunotherapies for B-CLL.

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