Activin-A co-opts IRF4 and AhR signaling to induce human regulatory T cells that restrain asthmatic responses

Proceedings of the National Academy of Sciences of the United States of America

Volumn 114, Issue 14, 2017, Pages 2891-2900

  Tousa, Sofia ^a   Semitekolou, Maria ^a   Morianos, Ioannis ^a   Banos, Aggelos ^a   Trochoutsou, Aikaterini I ^a   Brodie, Tess M ^b   Poulos, Nikolaos ^a   Samitas, Konstantinos ^a,c   Kapasa, Maria ^a   Konstantopoulos, Dimitris ^d   Paraskevopoulos, Giannis ^e   Gaga, Mina ^c   Hawrylowicz, Catherine M ^f   Sallusto, Federica ^b   Xanthou, Georgina ^a  

^a BIOMEDICAL RESEARCH FOUNDATION   (Greece)

^b INSTITUTE FOR RESEARCH IN BIOMEDICINE   (Switzerland)

^c SOTIRIA GENERAL HOSPITAL   (Greece)

^d BIOMEDICAL SCIENCES RESEARCH CENTER ALEXANDER FLEMING   (Greece)

^e 401 GENERAL MILITARY HOSPITAL OF ATHENS   (Greece)

^f KING'S COLLEGE LONDON   (United Kingdom)

Author keywords

Activin A; Allergic inflammation; Cytokines; Human T regulatory cells; Immune regulation

Indexed keywords

ACTIVIN A; AROMATIC HYDROCARBON RECEPTOR; INDUCIBLE T CELL COSTIMULATOR; INTERFERON REGULATORY FACTOR 4; INTERLEUKIN 10; ACTIVIN; AHR PROTEIN, HUMAN; BASIC HELIX LOOP HELIX TRANSCRIPTION FACTOR; ICOS PROTEIN, HUMAN; IL10 PROTEIN, HUMAN; INTERFERON REGULATORY FACTOR; INTERFERON REGULATORY FACTOR-4;

ADOPTIVE TRANSFER; ALLERGIC AIRWAY INFLAMMATION; ALLERGIC ASTHMA; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CELL DIFFERENTIATION; COMPLEX FORMATION; CONTROLLED STUDY; EFFECTOR CELL; EX VIVO STUDY; FEMALE; GENE EXPRESSION REGULATION; HUMAN; HUMAN CELL; IN VITRO STUDY; NONHUMAN; PNEUMONIA; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN FUNCTION; REGULATORY T LYMPHOCYTE; SIGNAL TRANSDUCTION; ANIMAL; ASTHMA; CD4+ T LYMPHOCYTE; DISEASE MODEL; DRUG EFFECT; GENETICS; HYPERSENSITIVITY; IMMUNOLOGY; METABOLISM; SCID MOUSE; TRANSPLANTATION;

ACTIVINS; ANIMALS; ASTHMA; BASIC HELIX-LOOP-HELIX TRANSCRIPTION FACTORS; CD4-POSITIVE T-LYMPHOCYTES; CELL DIFFERENTIATION; DISEASE MODELS, ANIMAL; GENE EXPRESSION REGULATION; HUMANS; HYPERSENSITIVITY; INDUCIBLE T-CELL CO-STIMULATOR PROTEIN; INTERFERON REGULATORY FACTORS; INTERLEUKIN-10; MICE, SCID; PROMOTER REGIONS, GENETIC; RECEPTORS, ARYL HYDROCARBON; SIGNAL TRANSDUCTION; T-LYMPHOCYTES, REGULATORY;

EID: 85016945979     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.1616942114     Document Type: Article

References (47)

1. Barnes PJ (2011) Pathophysiology of allergic inflammation. Immunol Rev 242(1):31-50.
2. Shevach EM, Thornton AM (2014) tTregs, pTregs, and iTregs: Similarities and differences. Immunol Rev 259(1):88-102.
3. Curotto de Lafaille MA, et al. (2008) Adaptive Foxp3+ regulatory T cell-dependent and -independent control of allergic inflammation. Immunity 29(1):114-126.
4. Roncarolo MG, Gregori S, Bacchetta R, Battaglia M (2014) Tr1 cells and the counterregulation of immunity: Natural mechanisms and therapeutic applications. Curr Top Microbiol Immunol 380:39-68.
5. Josefowicz SZ, et al. (2012) Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482(7385):395-399.
6. Akdis M, et al. (2004) Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper2 cells. J Exp Med 199(11):1567-1575.
7. Campbell JD, et al. (2009) Peptide immunotherapy in allergic asthma generates IL-10-dependent immunological tolerance associated with linked epitope suppression. J Exp Med 206(7):1535-1547.
8. Gandhi R, et al. (2010) Activation of the aryl hydrocarbon receptor induces human type1 regulatory T cell-like and Foxp3(+) regulatory T cells. Nat Immunol 11(9):846-853.
9. Apetoh L, et al. (2010) The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat Immunol 11(9):854-861.
10. Veldhoen M, Hirota K, Christensen J, O'Garra A, Stockinger B (2009) Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J Exp Med 206(1):43-49.
11. Hedger MP, de Kretser DM (2013) The activins and their binding protein, follistatin-Diagnostic and therapeutic targets in inflammatory disease and fibrosis. Cytokine Growth Factor Rev 24(3):285-295.
12. Kariyawasam HH, Semitekolou M, Robinson DS, Xanthou G (2011) Activin-A: A novel critical regulator of allergic asthma. Clin Exp Allergy 41(11):1505-1514.
13. Matzuk MM, et al. (1995) Functional analysis of activins during mammalian development. Nature 374(6520):354-356.
14. Matzuk MM, Kumar TR, Bradley A (1995) Different phenotypes for mice deficient in either activins or activin receptor type II. Nature 374(6520):356-360.
15. Chng Z, Vallier L, Pedersen R (2011) Activin/nodal signaling and pluripotency. Vitam Horm 85:39-58.
16. Hardy CL, Rolland JM, O'Hehir RE (2015) The immunoregulatory and fibrotic roles of activin A in allergic asthma. Clin Exp Allergy 45(10):1510-1522.
17. Huber S, et al. (2009) Activin a promotes the TGF-beta-induced conversion of CD4+ CD25- T cells into Foxp3+ induced regulatory T cells. J Immunol 182(8):4633-4640.
18. Semitekolou M, et al. (2009) Activin-A induces regulatory T cells that suppress T helper cell immune responses and protect from allergic airway disease. J Exp Med 206(8):1769-1785.
19. Kariyawasam HH, et al. (2009) Activin and transforming growth factor-beta signaling pathways are activated after allergen challenge in mild asthma. J Allergy Clin Immunol 124(3):454-462.
20. Karagiannidis C, et al. (2006) Activin A is an acute allergen-responsive cytokine and provides a link to TGF-beta-mediated airway remodeling in asthma. J Allergy Clin Immunol 117(1):111-118.
21. Zielinski CE, et al. (2012) Pathogen-induced human TH17 cells produce IFN-γ or IL-10 and are regulated by IL-1β. Nature 484(7395):514-518.
22. Becattini S, et al. (2015) T cell immunity. Functional heterogeneity of human memory CD4+ T cell clones primed by pathogens or vaccines. Science 347(6220):400-406.
23. Hammad H, et al. (2002) Monocyte-derived dendritic cells induce a house dust mitespecific Th2 allergic inflammation in the lung of humanized SCID mice: Involvement of CCR7. J Immunol 169(3):1524-1534.
24. Locci M, et al. (2016) Activin A programs the differentiation of human TFH cells. Nat Immunol 17(8):976-984.
25. Gagliani N, et al. (2013) Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med 19(6):739-746.
26. Rowlands JC, McEwan IJ, Gustafsson JA (1996) Trans-activation by the human aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator proteins: Direct interactions with basal transcription factors. Mol Pharmacol 50(3):538-548.
27. Shultz LD, Ishikawa F, Greiner DL (2007) Humanized mice in translational biomedical research. Nat Rev Immunol 7(2):118-130.
28. Perros F, Hoogsteden HC, Coyle AJ, Lambrecht BN, Hammad H (2009) Blockade of CCR4 in a humanized model of asthma reveals a critical role for DC-derived CCL17 and CCL22 in attracting Th2 cells and inducing airway inflammation. Allergy 64(7):995-1002.
29. Pot C, Apetoh L, Awasthi A, Kuchroo VK (2011) Induction of regulatory Tr1 cells and inhibition of T(H)17 cells by IL-27. Semin Immunol 23(6):438-445.
30. Pot C, et al. (2009) Cutting edge: IL-27 induces the transcription factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that coordinately act together to promote differentiation of IL-10-producing Tr1 cells. J Immunol 183(2):797-801.
31. Roncarolo MG, et al. (2006) Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 212:28-50.
32. Jones CP, Gregory LG, Causton B, Campbell GA, Lloyd CM (2012) Activin A and TGF-β promote T(H)9 cell-mediated pulmonary allergic pathology. J Allergy Clin Immunol 129(4):1000-10.e3.
33. Zhou L, Chong MM, Littman DR (2009) Plasticity of CD4+ T cell lineage differentiation. Immunity 30(5):646-655.
34. Taniguchi T, Ogasawara K, Takaoka A, Tanaka N (2001) IRF family of transcription factors as regulators of host defense. Annu Rev Immunol 19:623-655.
35. Rengarajan J, et al. (2002) Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression. J Exp Med 195(8):1003-1012.
36. Zheng Y, et al. (2009) Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458(7236):351-356.
37. Zeng H, Zhang R, Jin B, Chen L (2015) Type 1 regulatory T cells: A new mechanism of peripheral immune tolerance. Cell Mol Immunol 12(5):566-571.
38. Chung KF, et al. (2014) International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 43(2):343-373.
39. Yao Y, et al. (2015) Tr1 Cells, but not Foxp3+ regulatory T cells, suppress NLRP3 inflammasome activation via an IL-10-dependent mechanism. J Immunol 195(2):488-497.
40. Samitas K, et al. (2016) Activin-A is overexpressed in severe asthma and is implicated in angiogenic processes. Eur Respir J 47(3):769-782.
41. Sonar SS, et al. (2010) Antagonism of TIM-1 blocks the development of disease in a humanized mouse model of allergic asthma. J Clin Invest 120(8):2767-2781.
42. Xanthou G, et al. (2007) Osteopontin has a crucial role in allergic airway disease through regulation of dendritic cell subsets. Nat Med 13(5):570-578.
43. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using realtime quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25(4):402-408.
44. Kim D, et al. (2013) TopHat2: Accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 14(4):R36.
45. Moulos P, Hatzis P (2015) Systematic integration of RNA-Seq statistical algorithms for accurate detection of differential gene expression patterns. Nucleic Acids Res 43(4):e25.
46. Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15(12):550.
47. Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: A Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26(1): 139-40.