TH17 and TH22 cells: A confusion of antimicrobial response with tissue inflammation versus protection
2012; Elsevier BV; Volume: 129; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2012.05.003
ISSN1097-6825
AutoresMübeccel Akdiş, Óscar Palomares, Willem van de Veen, Marloes van Splunter, Cezmi A. Akdiş,
Tópico(s)Asthma and respiratory diseases
ResumoSubstantial progress in understanding mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumors, organ transplantation, chronic infections, and pregnancy is in an exciting developmental phase that might lead to a variety of targeted therapeutic approaches. Recent progress in the interaction between immune/inflammatory cell subsets through cytokines, particularly the extension of the knowledge on reciprocal regulation and counterbalance between subsets of TH1, TH2, TH9, TH17, TH22, T follicular helper cells and different subsets of regulatory T cells, as well as corresponding and co-orchestrating B-cell, natural killer cell, dendritic cell, and innate lymphoid cell subsets, offers new possibilities for immune intervention. Studies on new subsets confirm the important role of T cells in the instruction of tissue cells and also demonstrate the important role of feedback regulation for the polarization toward distinct T-cell subsets. TH17 and TH22 cells are 2 emerging TH cell subsets that link the immune response to tissue inflammation; IL-17A and IL-17F and IL-22 are their respective prototype cytokines. Although both cytokines play roles in immune defense to extracellular bacteria, IL-17 augments inflammation, whereas IL-22 plays a tissue-protective role. This review focuses on current knowledge on TH17 and TH22 cells and their role in inflammation, with special focus on the mechanisms of their generation and driving and effector cytokines, as well as their role in host defense, autoimmunity, and allergic diseases. Substantial progress in understanding mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumors, organ transplantation, chronic infections, and pregnancy is in an exciting developmental phase that might lead to a variety of targeted therapeutic approaches. Recent progress in the interaction between immune/inflammatory cell subsets through cytokines, particularly the extension of the knowledge on reciprocal regulation and counterbalance between subsets of TH1, TH2, TH9, TH17, TH22, T follicular helper cells and different subsets of regulatory T cells, as well as corresponding and co-orchestrating B-cell, natural killer cell, dendritic cell, and innate lymphoid cell subsets, offers new possibilities for immune intervention. Studies on new subsets confirm the important role of T cells in the instruction of tissue cells and also demonstrate the important role of feedback regulation for the polarization toward distinct T-cell subsets. TH17 and TH22 cells are 2 emerging TH cell subsets that link the immune response to tissue inflammation; IL-17A and IL-17F and IL-22 are their respective prototype cytokines. Although both cytokines play roles in immune defense to extracellular bacteria, IL-17 augments inflammation, whereas IL-22 plays a tissue-protective role. This review focuses on current knowledge on TH17 and TH22 cells and their role in inflammation, with special focus on the mechanisms of their generation and driving and effector cytokines, as well as their role in host defense, autoimmunity, and allergic diseases. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: June 2012. Credit may be obtained for these courses until May 31, 2014.Copyright Statement: Copyright © 2012-2014. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Mübeccel Akdis, MD, PhD, Oscar Palomares, PhD, Willem van de Veen, MSc, Marloes van Splunter, Dipl Biol, and Cezmi A. Akdis, MDActivity Objectives1.To identify the various CD4+ TH cell subsets, including TH1, TH2, TH9, TH17, TH22, and T follicular helper cells.2.To review the differentiation and cytokine signatures of the TH cell subsets.3.To understand the role of the TH cell subsets in disease.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: M. Akdis has received grants from the Swiss Nation Science Foundation and the European Union Commission. O. Palomares declares that he has no no relevant conflicts of interest.W. van de Veen has received grants from the Swiss National Science Foundation and the European Commission. M. van Splunter has received grants from CK-CARE. C. Akdis has received grants from Novartis, the European Union Commission, the Swiss National Science Foundation, the Global Allergy and Asthma European Network, and the Christine Kühne Center for Allergy Research and Education; has consulted for Actellion, Aventis, Stallergenes, and Allergopharma; is president of the European Academy of Allergy and Clinical Immunology; is a fellow and interest group member of the American Academy of Allergy, Asthma, & Immunology; is a former committee member of the Global Allergy and Asthma European Network; and is director of the Christine Kühne Center for Allergy Research and Education.GlossaryAUTOSOMAL DOMINANT HYPER-IgE SYNDROMEA condition that results from mutations in the signal transducer and activator of transcription 3 (STAT3) gene. STAT3 is a transcription factor.ANTIMICROBIAL PEPTIDES (AMPs)Components of the innate immune system that are capable of inserting into bacterial phospholipids to slow microbial growth. AMP levels are decreased in the skin of patients with atopic dermatitis.CHRONIC GRAFT-VERSUS-HOST DISEASE (GVHD)T cells from a hematopoietic stem cell transplant react against the recipient's antigens. Chronic GVHD is defined as the persistence or appearance of symptoms from 100 days after transplantation. Risk factors for chronic GVHD include a history of acute GVHD, older age of the recipient at the time of transplantation, transplantation from a multiparous female donor into a male recipient (with reactivity to Y chromosome–associated antigens), and incompatibility at minor histocompatibility loci.DENDRITIC CELLSHematopoietic cells that function as antigen-presenting cells for naive lymphocytes. Their name is derived from their multiple, thin membranous projections.DIGOXINA cardiac glycoside used for atrial fibrillation, heart failure, and supraventricular tachycardia. Digoxin inhibits the Na+/K+ ATPase pump in myocardial cells, causing increased intracellular Na+, which in turns results in increased Ca++ influx through the Na+/Ca++ exchange pump. The result is enhanced cardiac contractility. Digoxin also directly suppresses the atrioventricular node.γδ T CELLA subpopulation of T cells located at epithelial barriers and sites of inflammation. γδ T cells are capable of binding to antigens directly without MHC presentation. They can also react to MHC molecules without an associated peptide. In addition to playing a role in defense against multiple different types of bacteria, they can accumulate at inflammatory sites in patients with autoimmune disease.IFN-γA cytokine with a multitude of effects in addition to promoting CD4+ T-cell differentiation into TH1 cells. Other actions of IFN-γ include activation of macrophages, upregulation of MHC class II expression, maturation of CD8+ T cells into cytotoxic T cells, activation of endothelial cells and neutrophils, and promotion of antiviral defenses.KERATINOCYTEAn epidermal cell that produces keratins, sulfur-containing fibrous proteins that form the basis of epidermal tissues, such as hair or nails.MEMORY T CELLA subset of CD4+ and CD8+ cells characterized by the cell-surface marker CD45RO. They are capable of surviving for long periods of time without antigenic stimulation. Memory B cells have been demonstrated to survive into the tenth decade of life.NAIVE T CELLCD4 and CD8 T cells emigrate from the thymus as naive T cells. Naive T cells produce IL-2 but only low levels of other cytokines. They are not strong helpers to B cells. They can survive without antigen but require the presence of MHC molecules. Naive T cells circulate from the blood to the spleen and lymph nodes.PLASMACYTOID DENDRITIC CELLSA type of dendritic cell with a distinct histologic morphology that can produce high levels of type I interferon and are thought to play special roles in antiviral host defense and autoimmunity.POLYMORPHISMThe existence of a gene in several allelic forms.TOLL-LIKE RECEPTOR 6A Toll-like receptor that binds to lipoproteins and lipoteichoic acid found on pathogens, such as gram-positive bacteria and Mycoplasma species.The Editors wish to acknowledge Daniel A. Searing, MD, for preparing this glossary.The immune response of memory T cells is essential in the inflammation and immune regulation seen in patients with many diseases related to tissue inflammation, such as allergic rhinitis, asthma, and atopic dermatitis, as well as organ transplantation, tumors, autoimmunity, and infections. CD4+ naive T cells can differentiate into TH1, TH2, TH9, TH17, TH22, and T follicular helper cells depending on the vitamins and other substances in the micromilieu, the adjuvanicity of the innate immune response stimulating substances coexposed with the antigen, the status that defines the responsiveness of T cells, the type and developmental stage of antigen-presenting cells, and the cytokines in the microenvironment. On the basis of their respective effector cytokine profiles and interactions with resident tissue cells, these T-cell subsets can promote different types of inflammatory responses (Fig 1). For the development of a certain type of immune response and to display their effector functions, these T cells, dendritic cells (DCs), innate lymphoid cells, and tissue cells in the environment develop a cytokine milieu that represents the type of immune response. During the development of allergic disease, effector TH2 cells produce IL-4, IL-5, IL-9, and IL-13,1Akdis C.A. Akdis M. Mechanisms of allergen-specific immunotherapy.J Allergy Clin Immunol. 2011; 127: 18-29Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 2Akdis M. Akdis C.A. IgE class switching and cellular memory.Nat Immunol. 2012; 13: 312-314Crossref PubMed Scopus (12) Google Scholar and probably other recently identified interleukins are released from tissue cells and DCs, such as IL-25, IL-31, IL-33, which altogether contribute to TH2 response and inflammation.3Kang C.M. Jang A.S. Ahn M.H. Shin J.A. Kim J.H. Choi Y.S. et al.Interleukin-25 and interleukin-13 production by alveolar macrophages in response to particles.Am J Respir Cell Mol Biol. 2005; 33: 290-296Crossref PubMed Scopus (65) Google Scholar, 4Bilsborough J. Leung D.Y. Maurer M. Howell M. Boguniewicz M. Yao L. et al.IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis.J Allergy Clin Immunol. 2006; 117: 418-425Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 5Kakkar R. Lee R.T. The IL-33/ST2 pathway: therapeutic target and novel biomarker.Nat Rev Drug Discov. 2008; 7: 827-840Crossref PubMed Scopus (175) Google Scholar These cytokines play roles in allergen-specific IgE production, eosinophilia, and mucus production. TH1 cells, with their prototype cytokine IFN-γ, play a role in defense against intracellular pathogens and activation-induced cell death of the skin and mucosal epithelium and T cells.6Akdis C.A. Allergy and hypersensitivity: mechanisms of allergic disease.Curr Opin Immunol. 2006; 18: 718-726Crossref PubMed Scopus (56) Google Scholar, 7Akkoc T. de Koning P.J. Ruckert B. Barlan I. Akdis M. Akdis C.A. Increased activation-induced cell death of high IFN-gamma-producing T(H)1 cells as a mechanism of T(H)2 predominance in atopic diseases.J Allergy Clin Immunol. 2008; 121 (e1): 652-658Abstract Full Text Full Text PDF PubMed Scopus (53) Google ScholarMost of the functions attributed to TH1 cells are now better understood after the discovery of TH17 cells. TH17 cells are characterized by IL-17A, IL-17F, and IL-22 expression as major cytokines.8Burgler S. Ouaked N. Bassin C. Basinski T.M. Mantel P.Y. Siegmund K. et al.Differentiation and functional analysis of human T(H)17 cells.J Allergy Clin Immunol. 2009; 123 (e1-7): 588-595Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 9Harrington L.E. Hatton R.D. Mangan P.R. Turner H. Murphy T.L. 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Murphy K.M. et al.Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.Nat Immunol. 2005; 6: 1123-1132Crossref PubMed Scopus (2333) Google Scholar but its expression has also been detected in CD8+ T cells, γδ T cells, natural killer (NK) cells, and neutrophils.10Schmidt-Weber C.B. Akdis M. Akdis C.A. TH17 cells in the big picture of immunology.J Allergy Clin Immunol. 2007; 120: 247-254Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar Consistent with the broad expression pattern of its receptor, IL-17A acts on a variety of cells, which respond by upregulating the expression of proinflammatory cytokines, chemokines, and metalloproteases.In contrast to the homolog IL-17A, IL-17B and its receptor, IL-17RB, are not expressed in immune cells but instead in the spinal cord, testis, small intestine, pancreas, stomach, prostate, ovary, colon mucosa, and cartilage.11Shi Y. Ullrich S.J. Zhang J. Connolly K. Grzegorzewski K.J. Barber M.C. et al.A novel cytokine receptor-ligand pair. Identification, molecular characterization, and in vivo immunomodulatory activity.J Biol Chem. 2000; 275: 19167-19176Crossref PubMed Scopus (123) Google Scholar No specific receptors for IL-17C or IL-17D have been identified.12Li H. Chen J. Huang A. Stinson J. Heldens S. Foster J. et al.Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family.Proc Natl Acad Sci U S A. 2000; 97: 773-778Crossref PubMed Scopus (163) Google Scholar IL-17C induces production of proinflammatory cytokines and metalloproteases by certain cells12Li H. Chen J. Huang A. Stinson J. Heldens S. 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Cutting edge: IL-17D, a novel member of the IL-17 family, stimulates cytokine production and inhibits hemopoiesis.J Immunol. 2002; 169: 642-646Crossref PubMed Google ScholarIn addition, 2 new subsets of effector TH cells have been identified according to their cytokine signatures: TH9 and TH22 cells. TGF-β in the presence of IL-4 reprograms TH2 cell differentiation and leads to the development of TH9 cells that produce IL-9 and IL-10. TH9 cells lack suppressive function and promote tissue inflammation.15Veldhoen M. Uyttenhove C. van Snick J. Helmby H. Westendorf A. Buer J. et al.Transforming growth factor-beta “reprograms” the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset.Nat Immunol. 2008; 9: 1341-1346Crossref PubMed Scopus (441) Google Scholar TH22 cells are characterized by IL-22 production and contribute to epidermal hyperplasia in patients with inflammatory skin disease.16Eyerich S. Eyerich K. Pennino D. Carbone T. Nasorri F. 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Over the last few years, a tremendous advance in the knowledge of T-cell biology has been gained. Here we review the most recent findings in the field of TH17 and TH22 cells. The functions of TH17 and TH22 cytokines, their receptors, signal transduction pathways, and cellular sources and targets and their roles in immune regulation and cellular networks, host defense and other immune-regulatory conditions, and allergy and asthma are discussed.Mechanisms of TH17 cell generationThe discovery of TH17 cells was essential to increase our understanding of inflammatory processes because it was unclear how TH1 cells actually mediate inflammation in tissue.10Schmidt-Weber C.B. Akdis M. Akdis C.A. TH17 cells in the big picture of immunology.J Allergy Clin Immunol. 2007; 120: 247-254Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar Several studies in mice lacking essential components of the TH1–IFN-γ pathway demonstrated that these mice were not protected against but rather quite susceptible to different types of autoimmune diseases.25Pot C. Apetoh L. Awasthi A. Kuchroo V.K. Induction of regulatory Tr1 cells and inhibition of T(H)17 cells by IL-27.Semin Immunol. 2011; 23: 438-445Crossref PubMed Scopus (28) Google Scholar Although the main function of TH17 cells is supposed to be induction of protection against potentially harmful fungi and extracellular bacteria,26Ghoreschi K. Laurence A. Yang X.P. Hirahara K. O'Shea J.J. T helper 17 cell heterogeneity and pathogenicity in autoimmune disease.Trends Immunol. 2011; 32: 395-401Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar a large battery of experiments with IL-17 neutralizing antibodies, as well as relatively high levels of IL-17A and IL-17F detected in patients with multiple sclerosis, rheumatoid arthritis, and psoriasis, firmly revealed that TH17 cells also drive tissue inflammation in patients with several autoimmune diseases and allergy.27Peters A. Lee Y. Kuchroo V.K. The many faces of Th17 cells.Curr Opin Immunol. 2011; 23: 702-706Crossref PubMed Scopus (63) Google Scholar, 28Krueger J. Fretzin S. Suárez-Fariñas M. Haslett P. Phipps K. Cameron G. et al.IL-17A is essential for cell activation and inflammatory gene circuits in psoriasis.J Allergy Clin Immunol. 2012; ([in press])Google Scholar Among the IL-17 family members, IL-17A and IL-17F have the highest degree of homology; they are 50% identical at the protein level.29Starnes T. Robertson M.J. Sledge G. Kelich S. Nakshatri H. Broxmeyer H.E. et al.Cutting edge: IL-17F, a novel cytokine selectively expressed in activated T cells and monocytes, regulates angiogenesis and endothelial cell cytokine production.J Immunol. 2001; 167: 4137-4140Crossref PubMed Google Scholar IL-17F binds to the same receptor as IL-17A (IL-17RA), although with lower affinity.30Hymowitz S.G. Filvaroff E.H. Yin J.P. Lee J. Cai L. Risser P. et al.IL-17s adopt a cysteine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding.EMBO J. 2001; 20: 5332-5341Crossref PubMed Scopus (235) Google Scholar IL-17A and IL-17F form heterodimers, as expected from their structural similarities. There are 2 isoforms of IL-17F that are both produced by activated TH17 cells.9Harrington L.E. Hatton R.D. Mangan P.R. Turner H. Murphy T.L. Murphy K.M. et al.Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.Nat Immunol. 2005; 6: 1123-1132Crossref PubMed Scopus (2333) Google Scholar Like IL-17A, IL-17F acts on many cell types and induces similar proinflammatory cytokines and chemokines, as predicted on the basis of their structural homology and expression patterns.TH17 cells were definitely recognized as an independent effector TH cell subset after the identification of the retinoic acid receptor–related orphan receptor (ROR) γt/C2 in mice and human subjects, respectively, which is the master transcription factor involved in their development.27Peters A. Lee Y. Kuchroo V.K. The many faces of Th17 cells.Curr Opin Immunol. 2011; 23: 702-706Crossref PubMed Scopus (63) Google Scholar Generation of human TH17 cells and expression of IL-17A, IL-17F, and IL-26 are driven by RORC2, a nuclear transcription factor that belongs to the family of ROR proteins, which encompasses RORA, RORB, and RORC. Several isoforms varying on the N-terminal domain are described for all ROR genes. In contrast to other nuclear receptors, ROR family proteins bind as monomers to DNA containing ROR response elements through a highly conserved DNA-binding domain. A hinge domain and a C-terminal ligand–binding domain that can interact with both coactivators and corepressors and positively or negatively regulate transcription of target genes are also distinguished in this family of transcription factors.31Medvedev A. Yan Z.H. Hirose T. Giguere V. Jetten A.M. Cloning of a cDNA encoding the murine orphan receptor RZR/ROR gamma and characterization of its response element.Gene. 1996; 181: 199-206Crossref PubMed Scopus (66) Google Scholar Recent findings have demonstrated that TH17 differentiation is impaired by small chemical compounds, such as digoxin and SR1001, that directly target RORγt.32Solt L.A. Kumar N. Nuhant P. Wang Y. Lauer J.L. Liu J. et al.Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand.Nature. 2011; 472: 491-494Crossref PubMed Scopus (55) Google Scholar, 33Huh J.R. Leung M.W. Huang P. Ryan D.A. Krout M.R. Malapaka R.R. et al.Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORgammat activity.Nature. 2011; 472: 486-490Crossref PubMed Scopus (119) Google Scholar Also, a potent synthetic retinoid, Am80, has been demonstrated to improve chronic graft-versus-host disease by regulating TH1 and TH17 cells.34Nishimori H. Maeda Y. Teshima T. Sugiyama H. Kobayashi K. Yamasuji Y. et al.Synthetic retinoid Am80 ameliorates chronic graft-versus-host disease by down-regulating Th1 and Th17.Blood. 2012; 119: 285-295Crossref PubMed Scopus (21) Google Scholar Previous studies indicated that the aryl hydrocarbon receptor, a ligand-dependent transcription factor involved in mediating the toxicity of dioxin, was involved in TH17 cell–mediated autoimmunity to environmental toxins and that their natural agonists were essential for optimal TH17 cell differentiation.35Veldhoen M. Hirota K. Westendorf A.M. Buer J. Dumoutier L. Renauld J.C. et al.The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins.Nature. 2008; 453: 106-109Crossref PubMed Scopus (584) Google Scholar, 36Veldhoen M. Hirota K. Christensen J. O'Garra A. Stockinger B. Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells.J Exp Med. 2009; 206: 43-49Crossref PubMed Scopus (194) Google Scholar Altogether, these novel advances suggest that the development of small-molecular-weight compounds inhibiting or interfering with RORγt/RORC2 functions might well represent a promising therapeutic alternative for preventing TH17-mediated tissue inflammation and autoimmunity. The identification of TGF-β and IL-6 as essential factors for TH17 differentiation in mice also contributed to supporting the existence of a new functional TH cell subset.37Bettelli E. Carrier Y. Gao W. Korn T. Strom T.B. Oukka M. et al.Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.Nature. 2006; 441: 235-238Crossref PubMed Scopus (3085) Google Scholar, 38Veldhoen M. Hocking R.J. Atkins C.J. Locksley R.M. Stockinger B. 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