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Activin-A induces regulatory T cells that suppress T helper cell immune responses and protect from allergic airway disease.

Semitekolou M, Alissafi T, Aggelakopoulou M, Kourepini E, Kariyawasam HH, Kay AB, Robinson DS, Lloyd CM, Panoutsakopoulou V, Xanthou G - J. Exp. Med. (2009)

Bottom Line: This beneficial effect is associated with dramatically decreased maturation of draining lymph node dendritic cells.Therapeutic administration of recombinant activin-A during pulmonary allergen challenge suppresses Th2 responses and protects from allergic disease.Finally, we demonstrate that immune cells infiltrating the lungs from individuals with active allergic asthma, and thus nonregulated inflammatory response, exhibit significantly decreased expression of activin-A's responsive elements.

View Article: PubMed Central - PubMed

Affiliation: Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece.

ABSTRACT
Activin-A is a pleiotropic cytokine that participates in developmental, inflammatory, and tissue repair processes. Still, its effects on T helper (Th) cell-mediated immunity, critical for allergic and autoimmune diseases, are elusive. We provide evidence that endogenously produced activin-A suppresses antigen-specific Th2 responses and protects against airway hyperresponsiveness and allergic airway disease in mice. Importantly, we reveal that activin-A exerts suppressive function through induction of antigen-specific regulatory T cells that suppress Th2 responses in vitro and upon transfer in vivo. In fact, activin-A also suppresses Th1-driven responses, pointing to a broader immunoregulatory function. Blockade of interleukin 10 and transforming growth factor beta1 reverses activin-A-induced suppression. Remarkably, transfer of activin-A-induced antigen-specific regulatory T cells confers protection against allergic airway disease. This beneficial effect is associated with dramatically decreased maturation of draining lymph node dendritic cells. Therapeutic administration of recombinant activin-A during pulmonary allergen challenge suppresses Th2 responses and protects from allergic disease. Finally, we demonstrate that immune cells infiltrating the lungs from individuals with active allergic asthma, and thus nonregulated inflammatory response, exhibit significantly decreased expression of activin-A's responsive elements. Our results uncover activin-A as a novel suppressive factor for Th immunity and a critical controller of allergic airway disease.

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In vivo depletion of activin-A during pulmonary allergen challenge exacerbates allergic airway disease and Th2 responses. (A) Experimental protocol used to block endogenous activin-A during pulmonary challenge. (B) BAL differentials from mice treated with anti–activin-A or Ig control, or from the alum controls are expressed as means ± SEM (n = 5–8 mice per group in four separate experiments). Statistical significance was obtained by an unpaired Student's t test (*, P = 0.0345; **, P = 0.0476). (C) AHR is depicted. Results shown for PenH are expressed as means ± SEM (n = 5–8 mice per group in four separate experiments). Data were analyzed by two-way analysis of variance (ANOVA) for repeated measures, followed by an unpaired Student's t test (*, P = 0.0164; **, P = 0.00047). (D) Representative photomicrographs demonstrating lung inflammation (H&E-stained sections) and mucus secretion (PAS-stained sections). Histological scores of H&E-stained (***, P = 0.0009) and PAS-stained (***, P < 0.0001) sections. Error bars depict means of groups (n = 5–8 mice per group in four independent experiments). Bars, 100 µm. (E) DLN cells were restimulated ex vivo with OVA. Proliferation was measured by [3H]thymidine incorporation. Results are shown as means ± SEM of triplicate wells (n = 5–8 mice per group in four independent experiments; ***, P < 0.0001). IL-4 (***, P < 0.0001), IL-13 (***, P < 0.0001), IL-10 (***, P < 0.0001), and IFN-γ (***, P < 0.0001) in supernatants are shown. Results are means ± SEM of duplicate wells (n = 5–8 mice per group in four independent experiments). (F) OVA-specific IgE (**, P = 0.0060), IgG1 (*, P = 0.0165), and IgG2a (*, P = 0.0218) in the sera of mice. Results are means ± SEM (n = 5–8 mice per group in four independent experiments). (G) CCL11 (**, P = 0.0054), CCL17 (P = 0.9399), and CCL22 (P = 0.5000) in lung homogenates are shown. Results are means ± SEM (n = 5–8 mice per group in four separate experiments). (H) DLN cells from anti–activin-A– or Ig–treated mice were co-cultured with LN KJ1-26+CD4+ T cells (2:1) in the presence of OVA323-339 peptide, and proliferation was measured (**, P = 0.001). The results are means ± SEM (n = 5–8 mice per group in two independent experiments). Eos, eosinophils; LMs, lymphomononuclears; Macs, macrophages; Neuts, neutrophils.
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fig1: In vivo depletion of activin-A during pulmonary allergen challenge exacerbates allergic airway disease and Th2 responses. (A) Experimental protocol used to block endogenous activin-A during pulmonary challenge. (B) BAL differentials from mice treated with anti–activin-A or Ig control, or from the alum controls are expressed as means ± SEM (n = 5–8 mice per group in four separate experiments). Statistical significance was obtained by an unpaired Student's t test (*, P = 0.0345; **, P = 0.0476). (C) AHR is depicted. Results shown for PenH are expressed as means ± SEM (n = 5–8 mice per group in four separate experiments). Data were analyzed by two-way analysis of variance (ANOVA) for repeated measures, followed by an unpaired Student's t test (*, P = 0.0164; **, P = 0.00047). (D) Representative photomicrographs demonstrating lung inflammation (H&E-stained sections) and mucus secretion (PAS-stained sections). Histological scores of H&E-stained (***, P = 0.0009) and PAS-stained (***, P < 0.0001) sections. Error bars depict means of groups (n = 5–8 mice per group in four independent experiments). Bars, 100 µm. (E) DLN cells were restimulated ex vivo with OVA. Proliferation was measured by [3H]thymidine incorporation. Results are shown as means ± SEM of triplicate wells (n = 5–8 mice per group in four independent experiments; ***, P < 0.0001). IL-4 (***, P < 0.0001), IL-13 (***, P < 0.0001), IL-10 (***, P < 0.0001), and IFN-γ (***, P < 0.0001) in supernatants are shown. Results are means ± SEM of duplicate wells (n = 5–8 mice per group in four independent experiments). (F) OVA-specific IgE (**, P = 0.0060), IgG1 (*, P = 0.0165), and IgG2a (*, P = 0.0218) in the sera of mice. Results are means ± SEM (n = 5–8 mice per group in four independent experiments). (G) CCL11 (**, P = 0.0054), CCL17 (P = 0.9399), and CCL22 (P = 0.5000) in lung homogenates are shown. Results are means ± SEM (n = 5–8 mice per group in four separate experiments). (H) DLN cells from anti–activin-A– or Ig–treated mice were co-cultured with LN KJ1-26+CD4+ T cells (2:1) in the presence of OVA323-339 peptide, and proliferation was measured (**, P = 0.001). The results are means ± SEM (n = 5–8 mice per group in two independent experiments). Eos, eosinophils; LMs, lymphomononuclears; Macs, macrophages; Neuts, neutrophils.

Mentions: We initially investigated the in vivo role of activin-A in Th-mediated responses and, more specifically, in Th2-associated allergic airway inflammation, as activin-A is expressed during Th2-driven allergic responses (Rosendahl et al., 2001; Hardy et al., 2006; Karagiannidis et al., 2006). For this, we administered a neutralizing antibody to activin-A (or Ig control) right before pulmonary allergen (OVA) challenge of OVA/aluminum hydroxide (alum)–sensitized mice (experimental protocol described in Fig. 1 A).


Activin-A induces regulatory T cells that suppress T helper cell immune responses and protect from allergic airway disease.

Semitekolou M, Alissafi T, Aggelakopoulou M, Kourepini E, Kariyawasam HH, Kay AB, Robinson DS, Lloyd CM, Panoutsakopoulou V, Xanthou G - J. Exp. Med. (2009)

In vivo depletion of activin-A during pulmonary allergen challenge exacerbates allergic airway disease and Th2 responses. (A) Experimental protocol used to block endogenous activin-A during pulmonary challenge. (B) BAL differentials from mice treated with anti–activin-A or Ig control, or from the alum controls are expressed as means ± SEM (n = 5–8 mice per group in four separate experiments). Statistical significance was obtained by an unpaired Student's t test (*, P = 0.0345; **, P = 0.0476). (C) AHR is depicted. Results shown for PenH are expressed as means ± SEM (n = 5–8 mice per group in four separate experiments). Data were analyzed by two-way analysis of variance (ANOVA) for repeated measures, followed by an unpaired Student's t test (*, P = 0.0164; **, P = 0.00047). (D) Representative photomicrographs demonstrating lung inflammation (H&E-stained sections) and mucus secretion (PAS-stained sections). Histological scores of H&E-stained (***, P = 0.0009) and PAS-stained (***, P < 0.0001) sections. Error bars depict means of groups (n = 5–8 mice per group in four independent experiments). Bars, 100 µm. (E) DLN cells were restimulated ex vivo with OVA. Proliferation was measured by [3H]thymidine incorporation. Results are shown as means ± SEM of triplicate wells (n = 5–8 mice per group in four independent experiments; ***, P < 0.0001). IL-4 (***, P < 0.0001), IL-13 (***, P < 0.0001), IL-10 (***, P < 0.0001), and IFN-γ (***, P < 0.0001) in supernatants are shown. Results are means ± SEM of duplicate wells (n = 5–8 mice per group in four independent experiments). (F) OVA-specific IgE (**, P = 0.0060), IgG1 (*, P = 0.0165), and IgG2a (*, P = 0.0218) in the sera of mice. Results are means ± SEM (n = 5–8 mice per group in four independent experiments). (G) CCL11 (**, P = 0.0054), CCL17 (P = 0.9399), and CCL22 (P = 0.5000) in lung homogenates are shown. Results are means ± SEM (n = 5–8 mice per group in four separate experiments). (H) DLN cells from anti–activin-A– or Ig–treated mice were co-cultured with LN KJ1-26+CD4+ T cells (2:1) in the presence of OVA323-339 peptide, and proliferation was measured (**, P = 0.001). The results are means ± SEM (n = 5–8 mice per group in two independent experiments). Eos, eosinophils; LMs, lymphomononuclears; Macs, macrophages; Neuts, neutrophils.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2722168&req=5

fig1: In vivo depletion of activin-A during pulmonary allergen challenge exacerbates allergic airway disease and Th2 responses. (A) Experimental protocol used to block endogenous activin-A during pulmonary challenge. (B) BAL differentials from mice treated with anti–activin-A or Ig control, or from the alum controls are expressed as means ± SEM (n = 5–8 mice per group in four separate experiments). Statistical significance was obtained by an unpaired Student's t test (*, P = 0.0345; **, P = 0.0476). (C) AHR is depicted. Results shown for PenH are expressed as means ± SEM (n = 5–8 mice per group in four separate experiments). Data were analyzed by two-way analysis of variance (ANOVA) for repeated measures, followed by an unpaired Student's t test (*, P = 0.0164; **, P = 0.00047). (D) Representative photomicrographs demonstrating lung inflammation (H&E-stained sections) and mucus secretion (PAS-stained sections). Histological scores of H&E-stained (***, P = 0.0009) and PAS-stained (***, P < 0.0001) sections. Error bars depict means of groups (n = 5–8 mice per group in four independent experiments). Bars, 100 µm. (E) DLN cells were restimulated ex vivo with OVA. Proliferation was measured by [3H]thymidine incorporation. Results are shown as means ± SEM of triplicate wells (n = 5–8 mice per group in four independent experiments; ***, P < 0.0001). IL-4 (***, P < 0.0001), IL-13 (***, P < 0.0001), IL-10 (***, P < 0.0001), and IFN-γ (***, P < 0.0001) in supernatants are shown. Results are means ± SEM of duplicate wells (n = 5–8 mice per group in four independent experiments). (F) OVA-specific IgE (**, P = 0.0060), IgG1 (*, P = 0.0165), and IgG2a (*, P = 0.0218) in the sera of mice. Results are means ± SEM (n = 5–8 mice per group in four independent experiments). (G) CCL11 (**, P = 0.0054), CCL17 (P = 0.9399), and CCL22 (P = 0.5000) in lung homogenates are shown. Results are means ± SEM (n = 5–8 mice per group in four separate experiments). (H) DLN cells from anti–activin-A– or Ig–treated mice were co-cultured with LN KJ1-26+CD4+ T cells (2:1) in the presence of OVA323-339 peptide, and proliferation was measured (**, P = 0.001). The results are means ± SEM (n = 5–8 mice per group in two independent experiments). Eos, eosinophils; LMs, lymphomononuclears; Macs, macrophages; Neuts, neutrophils.
Mentions: We initially investigated the in vivo role of activin-A in Th-mediated responses and, more specifically, in Th2-associated allergic airway inflammation, as activin-A is expressed during Th2-driven allergic responses (Rosendahl et al., 2001; Hardy et al., 2006; Karagiannidis et al., 2006). For this, we administered a neutralizing antibody to activin-A (or Ig control) right before pulmonary allergen (OVA) challenge of OVA/aluminum hydroxide (alum)–sensitized mice (experimental protocol described in Fig. 1 A).

Bottom Line: This beneficial effect is associated with dramatically decreased maturation of draining lymph node dendritic cells.Therapeutic administration of recombinant activin-A during pulmonary allergen challenge suppresses Th2 responses and protects from allergic disease.Finally, we demonstrate that immune cells infiltrating the lungs from individuals with active allergic asthma, and thus nonregulated inflammatory response, exhibit significantly decreased expression of activin-A's responsive elements.

View Article: PubMed Central - PubMed

Affiliation: Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece.

ABSTRACT
Activin-A is a pleiotropic cytokine that participates in developmental, inflammatory, and tissue repair processes. Still, its effects on T helper (Th) cell-mediated immunity, critical for allergic and autoimmune diseases, are elusive. We provide evidence that endogenously produced activin-A suppresses antigen-specific Th2 responses and protects against airway hyperresponsiveness and allergic airway disease in mice. Importantly, we reveal that activin-A exerts suppressive function through induction of antigen-specific regulatory T cells that suppress Th2 responses in vitro and upon transfer in vivo. In fact, activin-A also suppresses Th1-driven responses, pointing to a broader immunoregulatory function. Blockade of interleukin 10 and transforming growth factor beta1 reverses activin-A-induced suppression. Remarkably, transfer of activin-A-induced antigen-specific regulatory T cells confers protection against allergic airway disease. This beneficial effect is associated with dramatically decreased maturation of draining lymph node dendritic cells. Therapeutic administration of recombinant activin-A during pulmonary allergen challenge suppresses Th2 responses and protects from allergic disease. Finally, we demonstrate that immune cells infiltrating the lungs from individuals with active allergic asthma, and thus nonregulated inflammatory response, exhibit significantly decreased expression of activin-A's responsive elements. Our results uncover activin-A as a novel suppressive factor for Th immunity and a critical controller of allergic airway disease.

Show MeSH
Related in: MedlinePlus