title: Activin-A induces regulatory T cells that suppress T helper cell immune responses and protect from allergic airway disease.
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.
authors.affiliation: Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Semitekolou
authors.forename: Themis
authors.initials: T
authors.lastname: Alissafi
authors.forename: Maria
authors.initials: M
authors.lastname: Aggelakopoulou
authors.forename: Evangelia
authors.initials: E
authors.lastname: Kourepini
authors.forename: Harsha H
authors.initials: HH
authors.lastname: Kariyawasam
authors.forename: Antony B
authors.initials: AB
authors.lastname: Kay
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Robinson
authors.forename: Clare M
authors.initials: CM
authors.lastname: Lloyd
authors.forename: Vily
authors.initials: V
authors.lastname: Panoutsakopoulou
authors.forename: Georgina
authors.initials: G
authors.lastname: Xanthou
mesh_terms: D028341:Activins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000328:Adult; D000818:Animals; D001249:Asthma / Q000209:etiology / Q000276:immunology / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D010047:Ovalbumin / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D055815:Young Adult
chemical_list: D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; C422405:activin A; D028341:Activins; D016753:Interleukin-10; D010047:Ovalbumin