Activin-A induces regulatory T cells that suppress T helper cell immune responses and protect from allergic airway disease.
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.
Semitekolou
Maria
M
Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece.
Alissafi
Themis
T
Aggelakopoulou
Maria
M
Kourepini
Evangelia
E
Kariyawasam
Harsha H
HH
Kay
Antony B
AB
Robinson
Douglas S
DS
Lloyd
Clare M
CM
Panoutsakopoulou
Vily
V
Xanthou
Georgina
G
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
D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; C422405:activin A; D028341:Activins; D016753:Interleukin-10; D010047:Ovalbumin