B cells regulate expression of CD40 ligand on activated T cells by lowering the mRNA level and through the release of soluble CD40

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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Chrysophanol Mitigates T Cell Activation by Regulating the Expression of CD40 Ligand in Activated T Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21176122 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6122 ◽

Cited By ~ 1

Author(s):

Hyun-Su Lee ◽

Gil-Saeng Jeong

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

T Cell Activation ◽

Cell Activation ◽

Cell Receptor ◽

Cd40 Ligand ◽

Mitogen Activated Protein Kinase ◽

Jurkat T Cells ◽

Activated T Cells

Since T lymphocytes act as mediators between innate and acquired immunity, playing a crucial role in chronic inflammation, regulation of T cell activation to suitable levels is important. Chrysophanol, a member of the anthraquinone family, is known to possess several bioactivities, including anti-microbial, anti-cancer, and hepatoprotective activities, however, little information is available on the inhibitory effects of chrysophanol on T cell activation. To elucidate whether chrysophanol regulates the activity of T cells, IL-2 expression in activated Jurkat T cells pretreated with chrysophanol was assessed. We showed that chrysophanol is not cytotoxic to Jurkat T cells under culture conditions using RPMI (Rosewell Park Memorial Institute) medium. Pretreatment with chrysophanol inhibited IL-2 production in T cells stimulated by CD3/28 antibodies or SEE-loaded Raji B cells. We also demonstrated that chrysophanol suppressed the expression of the CD40 ligand (CD40L) in activated T cells, and uncontrolled conjugation between B cells by pretreatment with chrysophanol reduced T cell activation. Besides, treatment with chrysophanol of Jurkat T cells blocked the NFκB signaling pathway, resulting in the abrogation of MAPK (mitogen-activated protein kinase) in activated T cells. These results provide novel insights into the suppressive effect of chrysophanol on T cell activation through the regulation of CD40L expression in T cell receptor-mediated stimulation conditions.

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THE CD40 LIGAND gp39, IS DEFECTIVE IN ACTIVATED T CELLS FROM PATIENTS WITH X-LINKED HYPER-IgM SYNDROME

PEDIATRICS ◽

10.1542/peds.94.2.280c ◽

1994 ◽

Vol 94 (2) ◽

pp. 280-280

Author(s):

Arden Levy ◽

Andrew Liu

Keyword(s):

T Cells ◽

B Cells ◽

Bacterial Infections ◽

Cd40 Ligand ◽

Research Groups ◽

Activated T Cells ◽

Immune Disorder ◽

Hyper Igm Syndrome ◽

Hyper Igm

Purpose of the Studies. Hyper-IgM immunodeficiency is characterized by recurrent bacterial infections, normal or elevated IgM, and markedly decreased IgG, IgA, and IgE. Previous research suggested that the T cells of these patients are defective in their ability to help B cells make functional antibody. CD40 ligand (CD4OL) is a membrane glycoprotein on activated T helper cells and binds the CD40 molecule expressed on B cells, and induces proliferation and immunoglobulin class switching (in conjunction with IL-4). The gene for the CD4OL has been mapped to position q26.3-q27.1 on chromosome X (same as the Hyper-IgM gene and the area of isotype switching). Several research groups sought to determine if the immunodeficiency in Hyper-IgM patients is due to defective CD4OL. Findings. The five papers listed above document the work of different research groups that simultaneously found abnormalities in the CD4OL gene in a total of 16 patients with X-linked Hyper-IgM syndrome. Different mutations of the CD4OL gene have been discovered, including point mutations, deletions, and nonsense sequences. Mutant version of CD4OL taken from Hyper IgM patients were unable to "help" B cells in vitro. Thus, deficient CD40/CD40L interactions between B and T cells results in severely impaired immunity. Restricted CD40L gene expression to T cells may ultimately allow gene therapy as treatment. Reviewers' Comments. A concise editorial by Jean Marx entitled "Cell Communication Failure Leads to Immune Disorder" describes this landmark research and accompanies the Spriggs article in the February 12th issue of Science (pp. 896-897). This discovery may not only lead to treatment of this disorder, but also modification of other less favorable immune responses.

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Polyclonal activation of immature B cells by preactivated T cells: the role of IL-4 and CD40 ligand

International Immunology ◽

10.1093/intimm/5.11.1445 ◽

1993 ◽

Vol 5 (11) ◽

pp. 1445-1450 ◽

Cited By ~ 24

Author(s):

Robert D. Brines ◽

Gerry G. B. Klaus

Keyword(s):

T Cells ◽

B Cells ◽

Cd40 Ligand ◽

Polyclonal Activation ◽

Immature B Cells

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EXPRESSION OF CD40 LIGAND ON ACTIVATED T-CELLS FROM NEWBORNS AND CHILDREN OF DIFFERENT AGES. 1701

Pediatric Research ◽

10.1203/00006450-199604001-01725 ◽

1996 ◽

Vol 39 ◽

pp. 286-286

Author(s):

Beth L Benjamin ◽

Richard A Palmer ◽

Josiah F Wedgwood

Keyword(s):

T Cells ◽

Cd40 Ligand ◽

Activated T Cells ◽

Different Ages

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NF-κB Is Involved in Regulation of CD40 Ligand Expression on Mycobacterium bovis Bacillus Calmette-Guérin-Activated Human T Cells

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.10.3.376-382.2003 ◽

2003 ◽

Vol 10 (3) ◽

pp. 376-382 ◽

Cited By ~ 2

Author(s):

Patricia Méndez-Samperio ◽

Hilda Ayala ◽

Abraham Vázquez

Keyword(s):

T Cells ◽

Mycobacterium Bovis ◽

De Novo ◽

Cd40 Ligand ◽

Nuclear Factor Κb ◽

Binding Activity ◽

Cell Surface Expression ◽

Membrane Expression ◽

Activated T Cells ◽

Cd40l Expression

ABSTRACT Interaction between CD40L (CD154) on activated T cells and its receptor CD40 on antigen-presenting cells has been reported to be important in the resolution of infection by mycobacteria. However, the mechanism(s) by which Mycobacterium bovis bacillus Calmette-Guérin (BCG) up-regulates membrane expression of CD40L molecules is poorly understood. This study was done to investigate the role of the nuclear factor κB (NF-κB) signaling pathway in the regulation of CD40L expression in human CD4+ T cells stimulated with BCG. Specific pharmacologic inhibition of the NF-κB pathway revealed that this signaling cascade was required in the regulation of CD40L expression on the surface of BCG-activated CD4+ T cells. These results were further supported by the fact that treatment of BCG-activated CD4+ T cells with these pharmacological inhibitors significantly down-regulated CD40L mRNA. In this study, inhibitor κBα (IκBα) and IκBβ protein production was not affected by the chemical protease inhibitors and, more importantly, BCG led to the rapid but transient induction of NF-κB activity. Our results also indicated that CD40L expression on BCG-activated CD4+ T cells resulted from transcriptional up-regulation of the CD40L gene by a mechanism which is independent of de novo protein synthesis. Interestingly, BCG-induced activation of NF-κB and the increased CD40L cell surface expression were blocked by the protein kinase C (PKC) inhibitors 1-[5-isoquinolinesulfonyl]-2-methylpiperazine and salicylate, both of which block phosphorylation of IκB. Moreover, rottlerin a Ca2+-independent PKC isoform inhibitor, significantly down-regulated CD40L mRNA in BCG-activated CD4+ T cells. These data strongly suggest that CD40L expression by BCG-activated CD4+ T cells is regulated via the PKC pathway and by NF-κB DNA binding activity.

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CD40 LIGAND GENE DEFECTS RESPONSIBLE FOR X-LINKED HYPER-IgM SYNDROME

PEDIATRICS ◽

10.1542/peds.94.2.280b ◽

1994 ◽

Vol 94 (2) ◽

pp. 280-280

Author(s):

Arden Levy ◽

Andrew Liu

Keyword(s):

T Cells ◽

B Cells ◽

Bacterial Infections ◽

Point Mutations ◽

Cd40 Ligand ◽

Research Groups ◽

Immune Disorder ◽

Hyper Igm Syndrome ◽

Hyper Igm

Purpose of the Studies. Hyper-IgM immunodeficiency is characterized by recurrent bacterial infections, normal or elevated IgM, and markedly decreased IgG, IgA, and IgE. Previous research suggested that the T cells of these patients are defective in their ability to help B cells make functional antibody. CD40 ligand (CD4OL) is a membrane glycoprotein on activated T helper cells and binds the CD40 molecule expressed on B cells, and induces proliferation and immunoglobulin class switching (in conjunction with IL-4). The gene for the CD4OL has been mapped to position q26.3-q27.1 on chromosome X (same as the Hyper-IgM gene and the area of isotype switching). Several research groups sought to determine if the immunodeficiency in Hyper-IgM patients is due to defective CD4OL. Findings. The five papers listed above document the work of different research groups that simultaneously found abnormalities in the CD4OL gene in a total of 16 patients with X-linked Hyper-IgM syndrome. Different mutations of the CD4OL gene have been discovered, including point mutations, deletions, and nonsense sequences. Mutant version of CD4OL taken from Hyper IgM patients were unable to "help" B cells in vitro. Thus, deficient CD40/CD40L interactions between B and T cells results in severely impaired immunity. Restricted CD40L gene expression to T cells may ultimately allow gene therapy as treatment. Reviewers' Comments. A concise editorial by Jean Marx entitled "Cell Communication Failure Leads to Immune Disorder" describes this landmark research and accompanies the Spriggs article in the February 12th issue of Science (pp. 896-897). This discovery may not only lead to treatment of this disorder, but also modification of other less favorable immune responses.

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CD40 LIGAND MUTATIONS IN X-LINKED IMMUNODEFICIENCY WITH HYPER-IgM

PEDIATRICS ◽

10.1542/peds.94.2.280d ◽

1994 ◽

Vol 94 (2) ◽

pp. 280-280

Author(s):

Arden Levy ◽

Andrew Liu

Keyword(s):

T Cells ◽

B Cells ◽

Bacterial Infections ◽

Point Mutations ◽

Cell Communication ◽

Cd40 Ligand ◽

Research Groups ◽

Immune Disorder ◽

Hyper Igm

Purpose of the Studies. Hyper-IgM immunodeficiency is characterized by recurrent bacterial infections, normal or elevated IgM, and markedly decreased IgG, IgA, and IgE. Previous research suggested that the T cells of these patients are defective in their ability to help B cells make functional antibody. CD40 ligand (CD4OL) is a membrane glycoprotein on activated T helper cells and binds the CD40 molecule expressed on B cells, and induces proliferation and immunoglobulin class switching (in conjunction with IL-4). The gene for the CD4OL has been mapped to position q26.3-q27.1 on chromosome X (same as the Hyper-IgM gene and the area of isotype switching). Several research groups sought to determine if the immunodeficiency in Hyper-IgM patients is due to defective CD4OL. Findings. The five papers listed above document the work of different research groups that simultaneously found abnormalities in the CD4OL gene in a total of 16 patients with X-linked Hyper-IgM syndrome. Different mutations of the CD4OL gene have been discovered, including point mutations, deletions, and nonsense sequences. Mutant version of CD4OL taken from Hyper IgM patients were unable to "help" B cells in vitro. Thus, deficient CD40/CD40L interactions between B and T cells results in severely impaired immunity. Restricted CD40L gene expression to T cells may ultimately allow gene therapy as treatment. Reviewers' Comments. A concise editorial by Jean Marx entitled "Cell Communication Failure Leads to Immune Disorder" describes this landmark research and accompanies the Spriggs article in the February 12th issue of Science (pp. 896-897). This discovery may not only lead to treatment of this disorder, but also modification of other less favorable immune responses.

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IMMUNOLOGIC REACTIONS TO HAPTENS ON AUTOLOGOUS CARRIERS

Journal of Experimental Medicine ◽

10.1084/jem.137.2.411 ◽

1973 ◽

Vol 137 (2) ◽

pp. 411-423 ◽

Cited By ~ 27

Author(s):

John W. Moorhead ◽

Curla S. Walters ◽

Henry N. Claman

Keyword(s):

T Cells ◽

B Cells ◽

Aminocaproic Acid ◽

Single Amino Acid ◽

Secondary Response ◽

Spleen Cells ◽

Activated T Cells ◽

Thymus Cells

Both thymus-derived (T) and bone marrow-derived (B) lymphocytes participate in the response to a hapten 4-hydroxy-3-iodo-5-nitrophenylacetic acid (NIP), coupled to a nonimmunogenic isologous carrier, mouse gamma globulin (MGG). Spleen cells from mice immunized with NIP-MGG show increased DNA synthesis in vitro when cultured with NIP-MGG. The participation of and requirement for T cells in the response was demonstrated by treating the spleen cells with anti-θ serum. This treatment resulted in a 77% inhibition of the antigen response. Furthermore, adoptively transferred normal thymus cells could be specifically "activated" by NIP-MGG in vivo and they responded secondarily to the antigen in vitro. The active participation of B cells in the secondary response was demonstrated by passing the immune spleen cells through a column coated with polyvalent anti-MGG serum. Column filtration reduced the number of NIP-specific plaque-forming cells and NIP-specific rosette-forming cells (both functions of B cells) and produced a 47% inhibition of the NIP-MGG response. The ability of the cells to respond to phytohemagglutinin (PHA) was not affected by column filtration showing that T cells were not being selectively removed. The participation of B cells in the in vitro NIP-MGG response was also shown by treatment of the spleen cells with antiserum specific for MGG and MGG determinants. B cells were removed by treatment with anti-IgM or polyvalent anti-MGG serum plus complement, resulting in a respective 46 and 49% inhibition of the response to NIP-MGG. (Treatment with anti-IgM serum had no effect on T cells.) The contribution of the hapten NIP to stimulation of T cells was investigated using NIP-MGG-activated thymus cells. These activated T cells responded in vitro very well to the NIP-MGG complex but not to the MGG carrier alone demonstrating the requirement of the hapten for T cell stimulation. The response was also partially inhibited (41%) by incubating the activated cells with NIP coupled to a single amino acid (epsilon-aminocaproic acid) before addition of NIP-MGG. These results demonstrated that T cells recognize the hapten NIP when it is coupled to the isologous carrier MGG.

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