Human interleukin-2 promotes proliferation of activated B cells via surface receptors similar to those of activated T 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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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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Activated B cells express receptors for, and proliferate in response to, pure interleukin 2.

Journal of Experimental Medicine ◽

10.1084/jem.160.4.1170 ◽

1984 ◽

Vol 160 (4) ◽

pp. 1170-1183 ◽

Cited By ~ 259

Author(s):

R H Zubler ◽

J W Lowenthal ◽

F Erard ◽

N Hashimoto ◽

R Devos ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

B Cells ◽

B Cell ◽

Interleukin 2 ◽

T Helper ◽

Spleen Cells ◽

Human Spleen ◽

Apparent Dissociation Constant ◽

Activated B Cells

In this study we investigated whether interleukin 2 (IL-2) acts on B cell proliferation and whether activated B cells express IL-2 receptors. First, the functional activity of immunoaffinity-purified or recombinant human IL-2 was studied in a B blast assay using positively selected murine surface Ig-positive cells that had been activated by lipopolysaccharide (LPS) plus anti-Ig antibodies (anti-Ig). In this assay, T cells were not detected by fluorescence-activated cell sorter analysis. It was found that both IL-2 preparations led to optimal B cell proliferation compared with supernatants obtained from murine or human spleen cells or murine cloned T helper cells. Second, we observed that the IL-2 requirement in this assay was about the same as in a proliferation assay using lectin-activated polyclonal murine Lyt-2-positive T cells. Third, analysis of the binding of radiolabeled immunoaffinity-purified IL-2 to B cells indicated that LPS plus anti-Ig-activated B cells expressed a mean of 3,500 IL-2 receptors per cell with an apparent dissociation constant of 150 pM. However, neither nonactivated B cells nor B cells activated by LPS alone exhibited significant specific IL-2 binding. The functional and the receptor data are consistent with the conclusion that IL-2 is a growth factor not only for T cells but also for B cells.

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Antibodies to HLA Class I α1 Domain Trigger Apoptosis of CD40-Activated Human B Lymphocytes

Blood ◽

10.1182/blood.v90.2.726 ◽

1997 ◽

Vol 90 (2) ◽

pp. 726-735 ◽

Cited By ~ 14

Author(s):

Laurent Genestier ◽

Geneviève Meffre ◽

Pierre Garrone ◽

Jean-Jacques Pin ◽

Yong-Jun Liu ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

B Lymphocytes ◽

Apoptotic Cell ◽

Interleukin 2 ◽

Hla Class I ◽

Class I ◽

Activated T Cells ◽

Hla Class I Molecules ◽

Activated B Cells

Abstract We analyzed herein whether antibodies to HLA class I α1 domain, which trigger apoptosis of activated T cells, may also control the growth/survival of human B lymphocytes. Addition of monoclonal antibody (MoAb) 90 (mouse IgG1) or YTH862 (rat IgG2b) was found to strongly inhibit the proliferation of CD40-activated total tonsil B cells as well as that of purified naive, germinal center, and memory B-cell subsets. This inhibitory effect was not prevented by addition of B-cell tropic factors, such as interleukin-2 (IL-2), IL-4, and IL-10, and was a result of induced B-cell apoptosis as shown by using a TUNEL assay and DNA electrophoresis. In contrast, engagement of another epitope of the α1 domain, as well as that of the α2 and α3 domains by specific anti-HLA class I MoAbs, failed to inhibit DNA synthesis and to induce apoptosis of CD40-activated B cells. As recently reported for acquisition of sensitivity to Fas (APO-1/CD95) -dependent apoptosis, susceptibility to MoAb90-and YTH862-induced death was restricted to CD40-activated B cells, because resting and anti–IgM-activated B cells did not undergo apoptosis after HLA class I engagement. Moreover, ligation of the B-cell receptor protected CD40-activated B cells from both HLA class I- and Fas-mediated growth inhibition and apoptosis. Taken together, these results show that engagement of the α1 domain of HLA class I induces apoptotic cell death of CD40-activated, but not of antigen-activated B cells, and would, therefore, suggest a possible role for HLA class I molecules in the control of B-cell homeostasis.

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Different Susceptibility of T and B Cells to Cladribine Depends On Their Levels of Deoxycytidine Kinase Activity Linked to Activation Status

Journal of Neuroimmune Pharmacology ◽

10.1007/s11481-021-09994-3 ◽

2021 ◽

Author(s):

Federico Carlini ◽

Federico Ivaldi ◽

Francesca Gualandi ◽

Ursula Boschert ◽

Diego Centonze ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Immune Cells ◽

Mrna Level ◽

Deoxycytidine Kinase ◽

T And B Cells ◽

Activated T Cells ◽

Important Relationship ◽

Activation Status ◽

Activated B Cells

Abstract Deoxycytidine kinase (dCK) and 5’ deoxynucleotidase (NT5C2) are involved in metabolism of cladribine (2CdA), the immunomodulatory drug for multiple sclerosis; by mediating phosphorylation (activation) or phosphorolysis (deactivation) of 2CdA, respectively, these enzymes promote or prevent its accumulation in the cell, which leads to cell death. In particular, lymphocytes which present with a high intracellular dCK/NT5C2 ratio are more sensitive to 2CdA than other immune cells. We aim at determining if the expression of these enzymes and/or their activity differ in specific progenitor and mature immune cells and are influenced by cellular activation and/or exposure to 2CdA. Flow cytometry analysis showed no difference in dCK/NT5C2 ratio in progenitor and mature immune cells. 2CdA induced apoptosis in stimulated T and B cells and unstimulated B cells. dCK expression was enhanced by 2CdA at mRNA and protein levels in activated T cells and mRNA level in activated B cells. dCK activity, measured through an in-house luminescence release enzyme assay was higher in activated T and B cells, and such an increase was abrogated in activated B cells, but not T cells, upon exposure to 2CdA. These results reveal an important relationship between dCK activity and the effect of 2CdA on B and T cells, according to their activation status. Further study is warranted to evaluate whether dCK activity could, in the future, be a suitable predictive biomarker of lymphocyte response to 2CdA. Graphical Abstract "Image missing"

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Detection and functional studies of p60-65 (Tac antigen) on activated human B cells.

Journal of Experimental Medicine ◽

10.1084/jem.160.5.1597 ◽

1984 ◽

Vol 160 (5) ◽

pp. 1597-1602 ◽

Cited By ~ 82

Author(s):

L K Jung ◽

T Hara ◽

S M Fu

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Interleukin 2 ◽

Receptor Expression ◽

Pokeweed Mitogen ◽

Activated T Cells ◽

Human B Cells ◽

Activated B Cells

A monoclonal antibody, AT-1, is shown to precipitate a p60-65 molecule identical to the Tac antigen. With AT-1, the expression of IL-2 receptors by normal activated human B cells from peripheral blood and tonsils is documented by biosynthetic and immunofluorescence studies. AT-1 precipitated a p60-65 protein from [35S]methionine-labeled activated B cells, similar to that from activated T cells. The interleukin 2 (IL-2) receptor appeared shortly after activation with anti-IgM and B cell-stimulatory factor(s). Its expression reached its peak at 60-72 h with approximately 50% of the B blasts stained by AT-1. Other modes of activation of B cells, by T cell-independent, formalin-treated staphylococci and Epstein-Barr virus, and by T cell-dependent pokeweed mitogen, also induced IL-2 receptor expression. The functional significance of this finding was investigated using recombinant IL-2 (rIL-2). While rIL-2 did not induce resting B cells to proliferate in the presence of anti-IgM, it induced activated B cells to proliferate in the absence of other factors. On the other hand, rIL-2 did not induce the differentiation of these activated B lymphocytes. These data suggest that IL-2 may play a significant role in B cell activation.

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The T cell-B cell interaction via OX40-OX40L is necessary for the T cell-dependent humoral immune response.

Journal of Experimental Medicine ◽

10.1084/jem.183.3.979 ◽

1996 ◽

Vol 183 (3) ◽

pp. 979-989 ◽

Cited By ~ 209

Author(s):

E Stüber ◽

W Strober

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Germinal Centers ◽

Antibody Treatment ◽

Activated T Cells ◽

Activated B Cells

Recent in vitro studies have established that activated B cells express OX40 ligand (L), a member of the tumor necrosis factor/nerve growth factor family of cytokines, and become stimulated to proliferate and secrete immunoglobulin (Ig) after cross-linking of OX40L by its counterreceptor OX40, which is expressed on activated T cells. In the present study we investigated the in vivo role of this receptor-ligand pair for the interaction of T and B cells in the course of the T-dependent B cell response against 2,4,6 trinitro-phenyl-keyhole limpet hemocyanin. First, we showed that OX40 is maximally expressed by T cells in the periarteriolar lymphoid sheath (PALS) 3 d after primary immunization. These OX40+ cells are located in close proximity to antigen-specific, activated B cells. Second, we demonstrated that blocking of OX40-OX40L interaction with polyclonal anti-OX40 antibody or with antibodies against certain peptide sequences within its extracellular domain resulted in a profound decrease of the anti-hapten IgG response, whereas the antihapten IgM response was grossly unchanged. Third, we showed that this antibody treatment leads to an inhibition of the development of PALS-associated B cell foci, whereas the formation of germinal centers remained intact. Finally, our data suggest that, whereas B cell memory development was not impaired by anti-OX40 administration, OX40-OX40L interaction seems to be crucial in the secondary immune response. We conclude from these data that the OX40-OX40L interaction in vivo is necessary for the differentiation of activated B cells into highly Ig-producing cells, but is not involved in other pathways of antigen-driven B cell differentiation such as memory cell development in the germinal centers.

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Antibodies to HLA Class I α1 Domain Trigger Apoptosis of CD40-Activated Human B Lymphocytes

Blood ◽

10.1182/blood.v90.2.726.726_726_735 ◽

1997 ◽

Vol 90 (2) ◽

pp. 726-735 ◽

Cited By ~ 1

Author(s):

Laurent Genestier ◽

Geneviève Meffre ◽

Pierre Garrone ◽

Jean-Jacques Pin ◽

Yong-Jun Liu ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

B Lymphocytes ◽

Apoptotic Cell ◽

Interleukin 2 ◽

Hla Class I ◽

Class I ◽

Activated T Cells ◽

Hla Class I Molecules ◽

Activated B Cells

We analyzed herein whether antibodies to HLA class I α1 domain, which trigger apoptosis of activated T cells, may also control the growth/survival of human B lymphocytes. Addition of monoclonal antibody (MoAb) 90 (mouse IgG1) or YTH862 (rat IgG2b) was found to strongly inhibit the proliferation of CD40-activated total tonsil B cells as well as that of purified naive, germinal center, and memory B-cell subsets. This inhibitory effect was not prevented by addition of B-cell tropic factors, such as interleukin-2 (IL-2), IL-4, and IL-10, and was a result of induced B-cell apoptosis as shown by using a TUNEL assay and DNA electrophoresis. In contrast, engagement of another epitope of the α1 domain, as well as that of the α2 and α3 domains by specific anti-HLA class I MoAbs, failed to inhibit DNA synthesis and to induce apoptosis of CD40-activated B cells. As recently reported for acquisition of sensitivity to Fas (APO-1/CD95) -dependent apoptosis, susceptibility to MoAb90-and YTH862-induced death was restricted to CD40-activated B cells, because resting and anti–IgM-activated B cells did not undergo apoptosis after HLA class I engagement. Moreover, ligation of the B-cell receptor protected CD40-activated B cells from both HLA class I- and Fas-mediated growth inhibition and apoptosis. Taken together, these results show that engagement of the α1 domain of HLA class I induces apoptotic cell death of CD40-activated, but not of antigen-activated B cells, and would, therefore, suggest a possible role for HLA class I molecules in the control of B-cell homeostasis.

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Integration of Calcium and Cyclic AMP Signaling Pathways by 14-3-3

Molecular and Cellular Biology ◽

10.1128/mcb.20.2.702-712.2000 ◽

2000 ◽

Vol 20 (2) ◽

pp. 702-712 ◽

Cited By ~ 74

Author(s):

Chi-Wing Chow ◽

Roger J. Davis

Keyword(s):

T Cells ◽

Cyclic Amp ◽

Signaling Pathways ◽

Interleukin 2 ◽

Camp Signaling ◽

Phosphorylation Sites ◽

Nuclear Factor ◽

Activated T Cells ◽

Transcription Activity ◽

Kinase A

ABSTRACT Calcium-stimulated nuclear factor of activated T cells (NFAT) transcription activity at the interleukin-2 promoter is negatively regulated by cyclic AMP (cAMP). This effect of cAMP is mediated, in part, by protein kinase A phosphorylation of NFAT. The mechanism of regulation involves the creation of a phosphorylation-dependent binding site for 14-3-3. Decreased NFAT phosphorylation caused by the calcium-stimulated phosphatase calcineurin, or mutation of the PKA phosphorylation sites, disrupted 14-3-3 binding and increased NFAT transcription activity. In contrast, NFAT phosphorylation caused by cAMP increased 14-3-3 binding and reduced NFAT transcription activity. The regulated interaction between NFAT and 14-3-3 provides a mechanism for the integration of calcium and cAMP signaling pathways.

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