Activin-A co-opts IRF4 and AhR signaling to induce human regulatory T cells that restrain asthmatic responses.
Type 1 regulatory T (Tr1) cells play a pivotal role in restraining human T-cell responses toward environmental allergens and protecting against allergic diseases. Still, the precise molecular cues that underlie their transcriptional and functional specification remain elusive. Here, we show that the cytokine activin-A instructs the generation of CD4+T cells that express the Tr1-cell-associated molecules IL-10, inducible T-Cell costimulator (ICOS), lymphocyte activation gene 3 protein (LAG-3), and CD49b, and exert strongly suppressive functions toward allergic responses induced by naive and in vivo-primed human T helper 2 cells. Moreover, mechanistic studies reveal that activin-A signaling induces the activation of the transcription factor interferon regulatory factor (IRF4), which, along with the environmental sensor aryl hydrocarbon receptor, forms a multipartite transcriptional complex that binds in IL-10 and ICOS promoter elements and controls gene expression in human CD4+T cells. In fact, IRF4 silencing abrogates activin-A-drivenIL10andICOSup-regulation and impairs the suppressive functions of human activin-A-induced Tr1-like (act-A-iTr1) cells. Importantly, using a humanized mouse model of allergic asthma, we demonstrate that adoptive transfer of human act-A-iTr1 cells, both in preventive and therapeutic protocols, confers significant protection against cardinal asthma manifestations, including pulmonary inflammation. Overall, our findings uncover an activin-A-induced IRF4-aryl hydrocarbon receptor (AhR)-dependent transcriptional network, which generates suppressive human Tr1 cells that may be harnessed for the control of allergic diseases.
Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece.
Sofia
S
Tousa
Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece.
Maria
M
Semitekolou
Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece.
Ioannis
I
Morianos
Molecular Biology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece.
Aggelos
A
Banos
Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece.
Aikaterini I
AI
Trochoutsou
Cellular Immunology Laboratory, Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland.
Tess M
TM
Brodie
Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece.
Nikolaos
N
Poulos
Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece.|7th Respiratory Medicine Department and Asthma Center, "Sotiria" Athens Chest Hospital, 115 27 Athens, Greece.
Konstantinos
K
Samitas
Molecular Biology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece.
Maria
M
Kapasa
Department of Molecular Biology and Genetics, Biomedical Sciences Research Center "Alexander Fleming," 16602 Athens, Greece.
Dimitris
D
Konstantopoulos
Department of Allergology, "401 General Military Hospital of Athens," 115 27 Athens, Greece.
Giannis
G
Paraskevopoulos
7th Respiratory Medicine Department and Asthma Center, "Sotiria" Athens Chest Hospital, 115 27 Athens, Greece.
Mina
M
Gaga
Department of Asthma, Allergy, and Respiratory Science, Kings College, London WC2R 2LS, United Kingdom.
Catherine M
0000-0002-2337-7463
CM
Hawrylowicz
Cellular Immunology Laboratory, Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland.
Federica
F
Sallusto
Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece; gxanthou@bioacademy.gr.
Georgina
G
Xanthou
D028341:Activins / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D006967:Hypersensitivity / Q000378:metabolism / Q000517:prevention & control; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D016513:Mice, SCID; D011401:Promoter Regions, Genetic; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D000099218:Interferon Regulatory Factor-4
D028341:Activins; D051792:Basic Helix-Loop-Helix Proteins; D060889:Inducible T-Cell Co-Stimulator Protein; D050835:Interferon Regulatory Factors; D016753:Interleukin-10; D018336:Receptors, Aryl Hydrocarbon; D000099218:Interferon Regulatory Factor-4; C111235:AHR protein, human; C556692:ICOS protein, human; C508609:IL10 protein, human; C422405:activin A
activin-A; allergic inflammation; cytokines; human T regulatory cells; immune regulation