Efficient Generation of Antigen-Specific Cytotoxic T Cells Using Retrovirally Transduced CD40-Activated B Cells

ABSTRACT Chemokines are likely to play important roles in the pathophysiology of diseases associated with Epstein-Barr virus (EBV). Here, we have analyzed the repertoire of chemokines expressed by EBV-infected B cells. EBV infection of B cells induced expression of TARC/CCL17 and MDC/CCL22, which are known to attract Th2 cells and regulatory T cells via CCR4, and also upregulated constitutive expression of MIP-1α/CCL3, MIP-1β/CCL4, and RANTES/CCL5, which are known to attract Th1 cells and cytotoxic T cells via CCR5. Accordingly, EBV-immortalized B cells secreted these chemokines, especially CCL3, CCL4, and CCL22, in large quantities. EBV infection or stable expression of LMP1 also induced CCL17 and CCL22 in a B-cell line, BJAB. The inhibitors of the TRAF/NF-κB pathway (BAY11-7082) and the p38/ATF2 pathway (SB202190) selectively suppressed the expression of CCL17 and CCL22 in EBV-immortalized B cells and BJAB-LMP1. Consistently, transient-transfection assays using CCL22 promoter-reporter constructs demonstrated that two NF-κB sites and a single AP-1 site were involved in the activation of the CCL22 promoter by LMP1. Finally, serum CCL22 levels were significantly elevated in infectious mononucleosis. Collectively, LMP1 induces CCL17 and CCL22 in EBV-infected B cells via activation of NF-κB and probably ATF2. Production of CCL17 and CCL22, which attract Th2 and regulatory T cells, may help EBV-infected B cells evade immune surveillance by Th1 cells. However, the concomitant production of CCL3, CCL4, and CCL5 by EBV-infected B cells may eventually attract Th1 cells and cytotoxic T cells, leading to elimination of EBV-infected B cells at latency III and to selection of those with limited expression of latent genes.

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P2.03-37 The Efficiency of Octamer-4 Specific Cytotoxic T Cells Induce By CD40-B Cells in Killing Lung Cancer Stem-Like Cells

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2018.08.1224 ◽

2018 ◽

Vol 13 (10) ◽

pp. S730

Author(s):

X. Zhang ◽

J. Xu ◽

F. Hu ◽

H. Wang ◽

X. Zheng ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

B Cells ◽

Cytotoxic T Cells

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The autoantigen-binding B cell repertoires of normal and of chronically graft-versus-host-diseased mice.

Journal of Experimental Medicine ◽

10.1084/jem.165.6.1675 ◽

1987 ◽

Vol 165 (6) ◽

pp. 1675-1687 ◽

Cited By ~ 54

Author(s):

A G Rolink ◽

T Radaszkiewicz ◽

F Melchers

Keyword(s):

T Cells ◽

B Cells ◽

B Cell ◽

The Other ◽

Cell Populations ◽

Foreign Antigen ◽

Alloreactive T Cells ◽

Polyclonal Activator ◽

Activated B Cells

A quantitative analysis of the frequencies of autoantibody-producing B cells in GVHD and in normal mice has been undertaken by generating collections of hybridomas of activated B cells. These hybridomas secreted sufficient quantities of Ig to allow binding analyses on a panel of autoantigens. B cells have been activated in a variety of ways. In vivo they were activated by injection of alloreactive T cells of one parent, leading to GVHD by a foreign antigen, sheep erythrocytes, in a secondary response, or by the polyclonal activator LPS. B cells from an experimentally unstimulated animal were used for an analysis of the normal background. In vitro B cells were activated by alloreactive T cells or by LPS. The frequencies of hybridomas and, therefore, of activated B cells producing autoantibodies to DNA or to kidney were not significantly different in mice activated by a graft-vs.-host T cell response as compared with B cell populations activated by any of the other procedures. They were found to compose 7.1-17.1% of the total repertoire of activated B cells. Moreover, the frequencies of autoantibody-producing activated B cells does not change with time after induction of the graft-vs.-host reaction. The pattern and frequencies of autoantigen-binding specificities to cytoskeleton, smooth muscle, nuclei, mitochondria, and DNA were not found to be different in any of the groups of hybridomas. The single notable exception, found in GVHD mice, were hybridomas producing autoantibodies to kidney proximal tubular brush border. These results allow the conclusion that autoantigen-binding B cells exist in an activated state in GVHD mice, as well as in mice activated by a foreign antigen or by a polyclonal activator, in B cell populations activated in vitro either by alloreactive T cells or by a polyclonal activator, and even in the background of experimentally unstimulated animals. T cell-mediated graft-vs.-host activation, in large part, does not lead to a selective expansion of autoantigen-binding B cells. The main difference between the graft-vs.-host-activated B cell repertoire and all others is that approximately 90% of teh autoantibodies were of the IgG class, whereas al autoantibodies found in the other groups were IgM.

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New insights in the biology of Hodgkin lymphoma

Hematology ◽

10.1182/asheducation.v2012.1.328.3798326 ◽

2012 ◽

Vol 2012 (1) ◽

pp. 328-334 ◽

Cited By ~ 42

Author(s):

Ralf Küppers

Keyword(s):

T Cells ◽

B Cells ◽

Signaling Pathways ◽

Hodgkin Lymphoma ◽

Tumor Cells ◽

Cytotoxic T Cells ◽

Cell Gene Expression ◽

Expression Program ◽

Multiple Signaling ◽

Cell Gene

Abstract The Hodgkin and Reed/Sternberg (HRS) tumor cells of classical Hodgkin lymphoma (HL) and the lymphocyte-predominant tumor cells of nodular lymphocyte–predominant HL are both derived from germinal center B cells. HRS cells, however, have largely lost their B-cell gene-expression program and coexpress genes typical of various types of hematopoietic cells. Multiple signaling pathways show a deregulated activity in HRS cells. The genetic lesions involved in the pathogenesis of HL are only partly known, but numerous members and regulators of the NF-κB and JAK/STAT signaling pathways are affected, suggesting an important role for these pathways in HL pathogenesis. Some genetic lesions involve epigenetic regulators, and there is emerging evidence that HRS cells have undergone extensive epigenetic alterations compared with normal B cells. HRS and lymphocyte-predominant cells are usually rare in the lymphoma tissue, and interactions with other cells in the microenvironment are likely critical for HL pathophysiology. T cells represent a main population of infiltrating cells, and it appears that HRS cells both inhibit cytotoxic T cells efficiently and also receive survival signals from Th cells in direct contact with them.

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Expansion of Functionally Active Alloantigen-Specific Regulatory T Cells Using Activated B Cells.

Transplantation Journal ◽

10.1097/00007890-201407151-00072 ◽

2014 ◽

Vol 98 ◽

pp. 24

Author(s):

S. McEwen ◽

A. Chakraborty ◽

R. Kornbluth ◽

J. Miller ◽

J. Mathew ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Regulatory T Cells ◽

Activated B Cells

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Selective inhibition of growth factor-dependent human B cell proliferation by monoclonal antibody AB1 to an antigen expressed by activated B cells.

Journal of Experimental Medicine ◽

10.1084/jem.160.6.1919 ◽

1984 ◽

Vol 160 (6) ◽

pp. 1919-1924 ◽

Cited By ~ 11

Author(s):

L K Jung ◽

S M Fu

Keyword(s):

Monoclonal Antibody ◽

Cell Proliferation ◽

T Cells ◽

B Cells ◽

B Cell ◽

Leukemic Cells ◽

Activated T Cells ◽

Igm Antibodies ◽

Stimulatory Factor ◽

Activated B Cells

A monoclonal antibody, AB1, was established with activated human B cells as immunogen. AB1 stained activated B cells but not activated T cells. Its selective reactivity to activated B cells was further documented by its nonreactivity to activated T cells, resting T and B cells, monocytes, granulocytes, bone marrow cells, leukemic cells, and cells from cell lines of T, B, and myeloid lineages. Upon activation, the antigen appeared on B cells as early as 3-4 h after stimulation and was fully expressed by 38 h. The expression of this antigen was not dependent on the presence of B cell stimulatory factor(s). Anti-IgM antibodies by themselves induced its expression. AB1 inhibited B cell proliferation that was induced by a low dose anti-IgM antibody and conditioned medium containing B cell stimulatory factor. It did not inhibit B cell proliferation induced by either high doses of anti-IgM antibodies or by formalinized Staphylococcus aureus. It also failed to inhibit T cell mitogenesis. The possibility exists that this antigen is related to the receptor for B cell stimulatory factor.

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Exhaustion of cytotoxic T cells during adoptive immunotherapy of virus carrier mice can be prevented by B cells or CD4+ T cells

European Journal of Immunology ◽

10.1002/1521-4141(200202)32:2<374::aid-immu374>3.0.co;2-9 ◽

2002 ◽

Vol 32 (2) ◽

pp. 374-382 ◽

Cited By ~ 31

Author(s):

Lukas Hunziker ◽

Paul Klenerman ◽

Rolf M. Zinkernagel ◽

Stephan Ehl

Keyword(s):

T Cells ◽

B Cells ◽

Adoptive Immunotherapy ◽

Cd4 T Cells ◽

Cytotoxic T Cells ◽

Virus Carrier

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Interleukin 2 induces antigen-reactive T cell lines to secrete BCGF-I.

Journal of Experimental Medicine ◽

10.1084/jem.158.6.2024 ◽

1983 ◽

Vol 158 (6) ◽

pp. 2024-2039 ◽

Cited By ~ 85

Author(s):

M Howard ◽

L Matis ◽

T R Malek ◽

E Shevach ◽

W Kell ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cell Line ◽

Cell Lines ◽

Interleukin 2 ◽

Activated T Lymphocytes ◽

T Cell Lines ◽

Activated B Cells

Antigen-activated T lymphocytes produce within 24 h of stimulation a factor that is indistinguishable biochemically and functionally from the B cell co-stimulating growth factor, BCGF-I, originally identified in induced EL4 supernatants: Supernatants from antigen-stimulated T cell lines are not directly mitogenic for resting B cells, but synergize in an H-2-unrestricted manner with anti-Ig activated B cells to produce polyclonal proliferation but not antibody-forming-cell development; biochemical studies reveal the B cell co-stimulating factor present in antigen-stimulated T cell line supernatants is identical by phenyl Sepharose chromatography and isoelectric focusing (IEF) to EL4 supernatant BCGF-I. We thus conclude that normal T cells produce BCGF-I in response to antigenic stimulation. Analysis of the mechanism of BCGF-I production by antigen-stimulated T cells showed that optimum amounts of BCGF-I were obtained as quickly as 24 h post-stimulation, and that the factor producing cells in the T cell line investigated bore the Lyt-1+2- phenotype. As few as 10(4) T cells produced sufficient BCGF-I to support the proliferation of 5 X 10(4) purified anti-Ig activated B cells. Finally, the activation of normal T cell lines to produce BCGF-I required either antigen presented in the context of syngeneic antigen-presenting cells (APC) or interleukin 2 (IL-2).

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Human macrophage inflammatory protein alpha (MIP-1 alpha) and MIP-1 beta chemokines attract distinct populations of lymphocytes.

Journal of Experimental Medicine ◽

10.1084/jem.177.6.1821 ◽

1993 ◽

Vol 177 (6) ◽

pp. 1821-1826 ◽

Cited By ~ 347

Author(s):

T J Schall ◽

K Bacon ◽

R D Camp ◽

J W Kaspari ◽

D V Goeddel

Keyword(s):

T Cells ◽

B Cells ◽

Cytotoxic T Cells ◽

Human Macrophage ◽

Immune Effector ◽

Effector Cells ◽

Inflammatory Protein ◽

And Migration ◽

Macrophage Inflammatory Protein

Lymphocyte trafficking is an essential process in immune and inflammatory functions which can be thought to contain at least two main components: adhesion and migration. Whereas adhesion molecules such as the selections are known to mediate the homing of leukocytes from the blood to the endothelium, the chemoattractant substances responsible for the migration of specific subsets of lymphocytes to sites of infection or inflammation are largely unknown. Here we show that two molecules in the chemokine (for chemoattractant cytokine) superfamily, human macrophage inflammatory protein 1 alpha (MIP-1 alpha) and MIP-1 beta, do not share identical attractant activities for lymphocyte subpopulations. When analyzed in vitro in microchemotaxis experiments, HuMIP-1 beta tends to attract CD4+ T lymphocytes, with some preference for T cells of the naive (CD45RA) phenotype. HuMIP-1 alpha, when tested in parallel with HuMIP-1 beta, is a more potent lymphocyte chemoattractant with a broader range of concentration-dependent chemoattractant specificities. HuMIP-1 alpha at a concentration of 100 pg/ml attracts B cells and cytotoxic T cells, whereas at higher concentrations (10 ng/ml), the migration of these cells appears diminished, and the migration of CD4+ T cells is enhanced. Thus, in this assay system, HuMIP-1 alpha and -1 beta have differential attractant activities for subsets of immune effector cells, with HuMIP-1 alpha having greater effects than HuMIP-1 beta, particularly on B cells.

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