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The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells.

Dienz O, Eaton SM, Bond JP, Neveu W, Moquin D, Noubade R, Briso EM, Charland C, Leonard WJ, Ciliberto G, Teuscher C, Haynes L, Rincon M - J. Exp. Med. (2009)

Bottom Line: IL-21 production by CD4(+) T cells is required for IL-6 to promote B cell antibody production in vitro.Thus, IL-6 promotes antibody production by promoting the B cell helper capabilities of CD4(+) T cells through increased IL-21 production.IL-6 could therefore be a potential coadjuvant to enhance humoral immunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine/Immunobiology Program, University of Vermont, Burlington, VT 05405, USA.

ABSTRACT
Interleukin (IL) 6 is a proinflammtory cytokine produced by antigen-presenting cells and nonhematopoietic cells in response to external stimuli. It was initially identified as a B cell growth factor and inducer of plasma cell differentiation in vitro and plays an important role in antibody production and class switching in vivo. However, it is not clear whether IL-6 directly affects B cells or acts through other mechanisms. We show that IL-6 is sufficient and necessary to induce IL-21 production by naive and memory CD4(+) T cells upon T cell receptor stimulation. IL-21 production by CD4(+) T cells is required for IL-6 to promote B cell antibody production in vitro. Moreover, administration of IL-6 with inactive influenza virus enhances virus-specific antibody production, and importantly, this effect is dependent on IL-21. Thus, IL-6 promotes antibody production by promoting the B cell helper capabilities of CD4(+) T cells through increased IL-21 production. IL-6 could therefore be a potential coadjuvant to enhance humoral immunity.

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Related in: MedlinePlus

Effects of IL-6 on the gene expression profile of CD4+ T cells early during activation. (A) FACS-sorted CD4+ T cells were activated with anti-CD3 and anti-CD28 in the absence or presence of IL-6 for 16 h. The gene expression profile from total RNA was examined by Affymetrix GeneChip analysis. In the volcano plot, open circles represent probe sets for which expression is changed more than twofold up or down after IL-6 treatment, whereas dots represent all other probe sets. The number of genes exceeding the threshold was the largest among the 10 datasets obtained by permutation of sample labels, yielding statistical significance of differential expression at P = 0.1 (the minimum value) and a false discovery rate <19% (the minimum being 10%). The blue line encloses 99% of the probe sets under the  hypothesis, obtained by permutation of sample labels. The IL-21 gene is marked with an arrow. (B) Heat maps representing the relative expression of genes among IL-6–treated and control samples. Genes were sorted within each group based on their fold change (top, highest fold induction; bottom, highest fold down-regulation). Expression statistics for each gene were centered, scaled, and mapped to a color scale. Red represents relatively low expression, whereas green represents relatively high expression. (C) Cells were purified and activated as in A, and IL-21 expression was measured by quantitative real-time RT-PCR. The means ± SEM of three experiments are shown. (D) CD4+ T cells were activated with anti-CD3 and anti-CD28 mAbs in the absence or presence of IL-6 for the indicated periods of time. Cell-culture supernatants were analyzed for IL-21 production by ELISA. The means ± SEM of four experiments are shown.
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fig1: Effects of IL-6 on the gene expression profile of CD4+ T cells early during activation. (A) FACS-sorted CD4+ T cells were activated with anti-CD3 and anti-CD28 in the absence or presence of IL-6 for 16 h. The gene expression profile from total RNA was examined by Affymetrix GeneChip analysis. In the volcano plot, open circles represent probe sets for which expression is changed more than twofold up or down after IL-6 treatment, whereas dots represent all other probe sets. The number of genes exceeding the threshold was the largest among the 10 datasets obtained by permutation of sample labels, yielding statistical significance of differential expression at P = 0.1 (the minimum value) and a false discovery rate <19% (the minimum being 10%). The blue line encloses 99% of the probe sets under the hypothesis, obtained by permutation of sample labels. The IL-21 gene is marked with an arrow. (B) Heat maps representing the relative expression of genes among IL-6–treated and control samples. Genes were sorted within each group based on their fold change (top, highest fold induction; bottom, highest fold down-regulation). Expression statistics for each gene were centered, scaled, and mapped to a color scale. Red represents relatively low expression, whereas green represents relatively high expression. (C) Cells were purified and activated as in A, and IL-21 expression was measured by quantitative real-time RT-PCR. The means ± SEM of three experiments are shown. (D) CD4+ T cells were activated with anti-CD3 and anti-CD28 mAbs in the absence or presence of IL-6 for the indicated periods of time. Cell-culture supernatants were analyzed for IL-21 production by ELISA. The means ± SEM of four experiments are shown.

Mentions: IL-6 has been associated with different aspects of T cell activation, differentiation, and survival (2). However, little is known about the changes in gene expression induced by IL-6 stimulation early during T cell activation. To further characterize early effects of IL-6 on CD4+ T cells, we performed microarray analysis. Sorted CD4+ NK1.1− T cells were activated with anti-CD3 and anti-CD28 mAbs in the absence or presence of IL-6 for 16 h. For each condition, three independent preparations of RNA were used for hybridization of gene arrays. For analysis of microarray data, we explored the use of the 1% contour on the joint distribution of fold change and p-value derived from sample label permutations (Fig. 1 A), which resulted in significance at P = 0.1, as well as identification of 343 genes, with a false discovery rate of 13%. 132 differentially regulated genes (190 probe sets) were found when using a twofold threshold on the probe set intensity ratio, IL-6 treated to untreated (Fig. 1 B; and Fig. S1 and Table S1, available at http://www.jem.org/cgi/content/full/jem.20081571/DC1). The microarray results were validated by real-time RT-PCR of several genes positively or negatively affected by the IL-6 treatment (Fig. S2).


The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells.

Dienz O, Eaton SM, Bond JP, Neveu W, Moquin D, Noubade R, Briso EM, Charland C, Leonard WJ, Ciliberto G, Teuscher C, Haynes L, Rincon M - J. Exp. Med. (2009)

Effects of IL-6 on the gene expression profile of CD4+ T cells early during activation. (A) FACS-sorted CD4+ T cells were activated with anti-CD3 and anti-CD28 in the absence or presence of IL-6 for 16 h. The gene expression profile from total RNA was examined by Affymetrix GeneChip analysis. In the volcano plot, open circles represent probe sets for which expression is changed more than twofold up or down after IL-6 treatment, whereas dots represent all other probe sets. The number of genes exceeding the threshold was the largest among the 10 datasets obtained by permutation of sample labels, yielding statistical significance of differential expression at P = 0.1 (the minimum value) and a false discovery rate <19% (the minimum being 10%). The blue line encloses 99% of the probe sets under the  hypothesis, obtained by permutation of sample labels. The IL-21 gene is marked with an arrow. (B) Heat maps representing the relative expression of genes among IL-6–treated and control samples. Genes were sorted within each group based on their fold change (top, highest fold induction; bottom, highest fold down-regulation). Expression statistics for each gene were centered, scaled, and mapped to a color scale. Red represents relatively low expression, whereas green represents relatively high expression. (C) Cells were purified and activated as in A, and IL-21 expression was measured by quantitative real-time RT-PCR. The means ± SEM of three experiments are shown. (D) CD4+ T cells were activated with anti-CD3 and anti-CD28 mAbs in the absence or presence of IL-6 for the indicated periods of time. Cell-culture supernatants were analyzed for IL-21 production by ELISA. The means ± SEM of four experiments are shown.
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Related In: Results  -  Collection

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fig1: Effects of IL-6 on the gene expression profile of CD4+ T cells early during activation. (A) FACS-sorted CD4+ T cells were activated with anti-CD3 and anti-CD28 in the absence or presence of IL-6 for 16 h. The gene expression profile from total RNA was examined by Affymetrix GeneChip analysis. In the volcano plot, open circles represent probe sets for which expression is changed more than twofold up or down after IL-6 treatment, whereas dots represent all other probe sets. The number of genes exceeding the threshold was the largest among the 10 datasets obtained by permutation of sample labels, yielding statistical significance of differential expression at P = 0.1 (the minimum value) and a false discovery rate <19% (the minimum being 10%). The blue line encloses 99% of the probe sets under the hypothesis, obtained by permutation of sample labels. The IL-21 gene is marked with an arrow. (B) Heat maps representing the relative expression of genes among IL-6–treated and control samples. Genes were sorted within each group based on their fold change (top, highest fold induction; bottom, highest fold down-regulation). Expression statistics for each gene were centered, scaled, and mapped to a color scale. Red represents relatively low expression, whereas green represents relatively high expression. (C) Cells were purified and activated as in A, and IL-21 expression was measured by quantitative real-time RT-PCR. The means ± SEM of three experiments are shown. (D) CD4+ T cells were activated with anti-CD3 and anti-CD28 mAbs in the absence or presence of IL-6 for the indicated periods of time. Cell-culture supernatants were analyzed for IL-21 production by ELISA. The means ± SEM of four experiments are shown.
Mentions: IL-6 has been associated with different aspects of T cell activation, differentiation, and survival (2). However, little is known about the changes in gene expression induced by IL-6 stimulation early during T cell activation. To further characterize early effects of IL-6 on CD4+ T cells, we performed microarray analysis. Sorted CD4+ NK1.1− T cells were activated with anti-CD3 and anti-CD28 mAbs in the absence or presence of IL-6 for 16 h. For each condition, three independent preparations of RNA were used for hybridization of gene arrays. For analysis of microarray data, we explored the use of the 1% contour on the joint distribution of fold change and p-value derived from sample label permutations (Fig. 1 A), which resulted in significance at P = 0.1, as well as identification of 343 genes, with a false discovery rate of 13%. 132 differentially regulated genes (190 probe sets) were found when using a twofold threshold on the probe set intensity ratio, IL-6 treated to untreated (Fig. 1 B; and Fig. S1 and Table S1, available at http://www.jem.org/cgi/content/full/jem.20081571/DC1). The microarray results were validated by real-time RT-PCR of several genes positively or negatively affected by the IL-6 treatment (Fig. S2).

Bottom Line: IL-21 production by CD4(+) T cells is required for IL-6 to promote B cell antibody production in vitro.Thus, IL-6 promotes antibody production by promoting the B cell helper capabilities of CD4(+) T cells through increased IL-21 production.IL-6 could therefore be a potential coadjuvant to enhance humoral immunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine/Immunobiology Program, University of Vermont, Burlington, VT 05405, USA.

ABSTRACT
Interleukin (IL) 6 is a proinflammtory cytokine produced by antigen-presenting cells and nonhematopoietic cells in response to external stimuli. It was initially identified as a B cell growth factor and inducer of plasma cell differentiation in vitro and plays an important role in antibody production and class switching in vivo. However, it is not clear whether IL-6 directly affects B cells or acts through other mechanisms. We show that IL-6 is sufficient and necessary to induce IL-21 production by naive and memory CD4(+) T cells upon T cell receptor stimulation. IL-21 production by CD4(+) T cells is required for IL-6 to promote B cell antibody production in vitro. Moreover, administration of IL-6 with inactive influenza virus enhances virus-specific antibody production, and importantly, this effect is dependent on IL-21. Thus, IL-6 promotes antibody production by promoting the B cell helper capabilities of CD4(+) T cells through increased IL-21 production. IL-6 could therefore be a potential coadjuvant to enhance humoral immunity.

Show MeSH
Related in: MedlinePlus