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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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Activin-A–induced regulatory T cells protect from allergic airway disease upon transfer in vivo. (A) CD4+ T cells (obtained as in Fig. 3) were treated with either PBS or r-activin-A and adoptively transferred to BALB/c mice before OVA/alum immunization and OVA challenge. (B) BAL differentials from mice that received r-activin-A– or PBS-treated CD4+ T cells, or from the alum controls. Results are expressed as means ± SEM (n = 5–7 mice per group in two separate experiments). Statistical significance was obtained by an unpaired Student's t test (*, P = 0.0407; ***, P = 0.0007). (C) AHR is depicted. Results shown for PenH are expressed as means (n = 5–7 mice per group in two separate experiments). Data were analyzed by two-way ANOVA for repeated measures, followed by an unpaired Student's t test (*, P = 0.0341; **, P = 0.0003; ***, P = 0.0004; ****, P = 0.0017). (D) Representative photomicrographs and histological scores of H&E-stained (***, P < 0.0001) and PAS-stained (***, P = 0.0004) sections. Error bars depict means of groups. Results are means ± SEM (n = 5–7 mice per group in two independent experiments). Bars, 100 µm. (E) DLN cells were restimulated ex vivo with OVA. Proliferation was measured (***, P = 0.0002). IL-4 (***, P < 0.0001), IL-13 (***, P < 0.0001), and IL-10 (***, P = 0.0008) in supernatants are shown. Results are shown as means ± SEM (n = 5–7 mice per group in two separate experiments). (F) OVA-specific IgE (**, P = 0.0009), IgG1 (P = 0.1259), and IgG2a (P = 0.4556) in the sera of mice. Results are means ± SEM (n = 5–7 mice per group in two independent experiments). (G) Flow cytometry panels of gated CD3−CD11c+ DLN cells from recipient mice stained for I-Ad. Numbers above boxed areas indicate the percentage of DLN cells in the outlined gate. The mean fluorescence intensity (MFI) of CD3−CD11c+I-Ad+ cells in DLNs of mice that received CD4+ T cells treated with PBS or r-activin-A is depicted (***, P < 0.0001). Values are means ± SEM (n = 5–7 mice per group in two separate experiments). Eos, eosinophils; FS, forward scatter; LMs, lymphomononuclears; Macs, macrophages; Neuts, neutrophils.
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fig5: Activin-A–induced regulatory T cells protect from allergic airway disease upon transfer in vivo. (A) CD4+ T cells (obtained as in Fig. 3) were treated with either PBS or r-activin-A and adoptively transferred to BALB/c mice before OVA/alum immunization and OVA challenge. (B) BAL differentials from mice that received r-activin-A– or PBS-treated CD4+ T cells, or from the alum controls. Results are expressed as means ± SEM (n = 5–7 mice per group in two separate experiments). Statistical significance was obtained by an unpaired Student's t test (*, P = 0.0407; ***, P = 0.0007). (C) AHR is depicted. Results shown for PenH are expressed as means (n = 5–7 mice per group in two separate experiments). Data were analyzed by two-way ANOVA for repeated measures, followed by an unpaired Student's t test (*, P = 0.0341; **, P = 0.0003; ***, P = 0.0004; ****, P = 0.0017). (D) Representative photomicrographs and histological scores of H&E-stained (***, P < 0.0001) and PAS-stained (***, P = 0.0004) sections. Error bars depict means of groups. Results are means ± SEM (n = 5–7 mice per group in two independent experiments). Bars, 100 µm. (E) DLN cells were restimulated ex vivo with OVA. Proliferation was measured (***, P = 0.0002). IL-4 (***, P < 0.0001), IL-13 (***, P < 0.0001), and IL-10 (***, P = 0.0008) in supernatants are shown. Results are shown as means ± SEM (n = 5–7 mice per group in two separate experiments). (F) OVA-specific IgE (**, P = 0.0009), IgG1 (P = 0.1259), and IgG2a (P = 0.4556) in the sera of mice. Results are means ± SEM (n = 5–7 mice per group in two independent experiments). (G) Flow cytometry panels of gated CD3−CD11c+ DLN cells from recipient mice stained for I-Ad. Numbers above boxed areas indicate the percentage of DLN cells in the outlined gate. The mean fluorescence intensity (MFI) of CD3−CD11c+I-Ad+ cells in DLNs of mice that received CD4+ T cells treated with PBS or r-activin-A is depicted (***, P < 0.0001). Values are means ± SEM (n = 5–7 mice per group in two separate experiments). Eos, eosinophils; FS, forward scatter; LMs, lymphomononuclears; Macs, macrophages; Neuts, neutrophils.

Mentions: We next asked whether activin-A–induced regulatory T cells can confer protection against Th-mediated disease in vivo. To address this, we adoptively transferred r-activin-A (or control)–treated CD4+ T cells (obtained as in Fig. 3) into BALB/c mice before OVA/alum immunization and OVA aerosol challenge (experimental protocol in Fig. 5 A). Remarkably, transfer of r-activin-A–treated OVA-primed CD4+ T cells resulted in a significant attenuation of all cardinal features of allergic airway disease (Fig. 5). This was demonstrated by significantly decreased total numbers of BAL cells and, notably, eosinophils in mice adoptively transferred with r-activin-A–treated OVA-primed CD4+ T cells as compared with mice transferred with control-treated CD4+ T cells (Fig. 5 B). More importantly, there was a dramatic decrease in AHR responses in mice that received r-activin-A–treated OVA-primed CD4+ T cells that reached levels similar to those of alum controls (Fig. 5 C). A significant decrease (approximately threefold in histological score) was also observed in leukocytic infiltration (Fig. 5 D) and in mucus secretion (approximately threefold; Fig. 5 D) in the lungs of mice transferred with r-activin-A–treated CD4+ T cells, as compared with controls.


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)

Activin-A–induced regulatory T cells protect from allergic airway disease upon transfer in vivo. (A) CD4+ T cells (obtained as in Fig. 3) were treated with either PBS or r-activin-A and adoptively transferred to BALB/c mice before OVA/alum immunization and OVA challenge. (B) BAL differentials from mice that received r-activin-A– or PBS-treated CD4+ T cells, or from the alum controls. Results are expressed as means ± SEM (n = 5–7 mice per group in two separate experiments). Statistical significance was obtained by an unpaired Student's t test (*, P = 0.0407; ***, P = 0.0007). (C) AHR is depicted. Results shown for PenH are expressed as means (n = 5–7 mice per group in two separate experiments). Data were analyzed by two-way ANOVA for repeated measures, followed by an unpaired Student's t test (*, P = 0.0341; **, P = 0.0003; ***, P = 0.0004; ****, P = 0.0017). (D) Representative photomicrographs and histological scores of H&E-stained (***, P < 0.0001) and PAS-stained (***, P = 0.0004) sections. Error bars depict means of groups. Results are means ± SEM (n = 5–7 mice per group in two independent experiments). Bars, 100 µm. (E) DLN cells were restimulated ex vivo with OVA. Proliferation was measured (***, P = 0.0002). IL-4 (***, P < 0.0001), IL-13 (***, P < 0.0001), and IL-10 (***, P = 0.0008) in supernatants are shown. Results are shown as means ± SEM (n = 5–7 mice per group in two separate experiments). (F) OVA-specific IgE (**, P = 0.0009), IgG1 (P = 0.1259), and IgG2a (P = 0.4556) in the sera of mice. Results are means ± SEM (n = 5–7 mice per group in two independent experiments). (G) Flow cytometry panels of gated CD3−CD11c+ DLN cells from recipient mice stained for I-Ad. Numbers above boxed areas indicate the percentage of DLN cells in the outlined gate. The mean fluorescence intensity (MFI) of CD3−CD11c+I-Ad+ cells in DLNs of mice that received CD4+ T cells treated with PBS or r-activin-A is depicted (***, P < 0.0001). Values are means ± SEM (n = 5–7 mice per group in two separate experiments). Eos, eosinophils; FS, forward scatter; LMs, lymphomononuclears; Macs, macrophages; Neuts, neutrophils.
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Related In: Results  -  Collection

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fig5: Activin-A–induced regulatory T cells protect from allergic airway disease upon transfer in vivo. (A) CD4+ T cells (obtained as in Fig. 3) were treated with either PBS or r-activin-A and adoptively transferred to BALB/c mice before OVA/alum immunization and OVA challenge. (B) BAL differentials from mice that received r-activin-A– or PBS-treated CD4+ T cells, or from the alum controls. Results are expressed as means ± SEM (n = 5–7 mice per group in two separate experiments). Statistical significance was obtained by an unpaired Student's t test (*, P = 0.0407; ***, P = 0.0007). (C) AHR is depicted. Results shown for PenH are expressed as means (n = 5–7 mice per group in two separate experiments). Data were analyzed by two-way ANOVA for repeated measures, followed by an unpaired Student's t test (*, P = 0.0341; **, P = 0.0003; ***, P = 0.0004; ****, P = 0.0017). (D) Representative photomicrographs and histological scores of H&E-stained (***, P < 0.0001) and PAS-stained (***, P = 0.0004) sections. Error bars depict means of groups. Results are means ± SEM (n = 5–7 mice per group in two independent experiments). Bars, 100 µm. (E) DLN cells were restimulated ex vivo with OVA. Proliferation was measured (***, P = 0.0002). IL-4 (***, P < 0.0001), IL-13 (***, P < 0.0001), and IL-10 (***, P = 0.0008) in supernatants are shown. Results are shown as means ± SEM (n = 5–7 mice per group in two separate experiments). (F) OVA-specific IgE (**, P = 0.0009), IgG1 (P = 0.1259), and IgG2a (P = 0.4556) in the sera of mice. Results are means ± SEM (n = 5–7 mice per group in two independent experiments). (G) Flow cytometry panels of gated CD3−CD11c+ DLN cells from recipient mice stained for I-Ad. Numbers above boxed areas indicate the percentage of DLN cells in the outlined gate. The mean fluorescence intensity (MFI) of CD3−CD11c+I-Ad+ cells in DLNs of mice that received CD4+ T cells treated with PBS or r-activin-A is depicted (***, P < 0.0001). Values are means ± SEM (n = 5–7 mice per group in two separate experiments). Eos, eosinophils; FS, forward scatter; LMs, lymphomononuclears; Macs, macrophages; Neuts, neutrophils.
Mentions: We next asked whether activin-A–induced regulatory T cells can confer protection against Th-mediated disease in vivo. To address this, we adoptively transferred r-activin-A (or control)–treated CD4+ T cells (obtained as in Fig. 3) into BALB/c mice before OVA/alum immunization and OVA aerosol challenge (experimental protocol in Fig. 5 A). Remarkably, transfer of r-activin-A–treated OVA-primed CD4+ T cells resulted in a significant attenuation of all cardinal features of allergic airway disease (Fig. 5). This was demonstrated by significantly decreased total numbers of BAL cells and, notably, eosinophils in mice adoptively transferred with r-activin-A–treated OVA-primed CD4+ T cells as compared with mice transferred with control-treated CD4+ T cells (Fig. 5 B). More importantly, there was a dramatic decrease in AHR responses in mice that received r-activin-A–treated OVA-primed CD4+ T cells that reached levels similar to those of alum controls (Fig. 5 C). A significant decrease (approximately threefold in histological score) was also observed in leukocytic infiltration (Fig. 5 D) and in mucus secretion (approximately threefold; Fig. 5 D) in the lungs of mice transferred with r-activin-A–treated CD4+ T cells, as compared with controls.

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