TH17 cells in the big picture of immunology
2007; Elsevier BV; Volume: 120; Issue: 2 Linguagem: Inglês
10.1016/j.jaci.2007.06.039
ISSN1097-6825
AutoresCarsten B. Schmidt‐Weber, Mübeccel Akdiş, Cezmi A. Akdiş,
Tópico(s)IL-33, ST2, and ILC Pathways
ResumoThe pathogenesis of chronic inflammatory diseases is assumed to depend on activated T cells interacting with resident tissue cells or migratory inflammatory cells. The discovery of new T-cell subsets such as the IL-17–producing TH17 and T-regulatory cells innovated our understanding of T-cell biology. 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. The understanding of IL-17 and TH17 differentiation pathways has also changed the perspective of immunologists regarding the basis of chronic tissue inflammation, particularly where TH1 cells were considered as driving force of the pathology. This review summarizes the recent developments on TH cell subsets and integrates these findings into existing concepts of immunopathologic mechanisms. The pathogenesis of chronic inflammatory diseases is assumed to depend on activated T cells interacting with resident tissue cells or migratory inflammatory cells. The discovery of new T-cell subsets such as the IL-17–producing TH17 and T-regulatory cells innovated our understanding of T-cell biology. 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. The understanding of IL-17 and TH17 differentiation pathways has also changed the perspective of immunologists regarding the basis of chronic tissue inflammation, particularly where TH1 cells were considered as driving force of the pathology. This review summarizes the recent developments on TH cell subsets and integrates these findings into existing concepts of immunopathologic mechanisms. The discovery of new T-cell subsets changed our concepts of immune regulation and immunopathology. Antigen-specific immune responses are dependent on B and T cells, characterized by their antigen-specific receptors. In contrast with B cells, T cells do not have direct antigen/allergen contact and play a discriminative role regarding the type and the place of immune responses to be initiated. Initially only 2 subsets were described: IFN-γ–secreting TH1 cells, assumed to play a role in inflammatory delayed type hypersensitivity, and a TH2 subset characterized for IL-3, IL-4, IL-5, IL-9, and IL-13 secretion mediating humoral responses. IL-2 expression was observed for both subsets. Murine TH2 cells do also express IL-10,1Schmidt-Weber C.B. Alexander S.I. Henault L.E. James L. Lichtman A.H. IL-4 enhances IL-10 gene expression in murine Th2 cells in the absence of TCR engagement.J Immunol. 1999; 162: 238-244PubMed Google Scholar whereas IL-10 in human beings could not be attributed to either subset2Sornasse T. Larenas P.V. Davis K.A. de Vries J.E. Yssel H. Differentiation and stability of T helper 1 and 2 cells derived from naive human neonatal CD4+ T cells, analyzed at the single-cell level.J Exp Med. 1996; 184: 473-483Crossref PubMed Scopus (242) Google Scholar and is discussed as a separate subset (T-regulatory 1 [Tr1] cells). Both TH1 and TH2 cells originate from naive T cells (Fig 1), which polarize on initial antigen contact either to TH1 or TH2 cells, when IL-12 or IFN-γ or IL-4 respectively induce a cascade of events resulting in genetic imprinting. This process is assumed to modulate chromatin structures as has been shown for IL-4–induced GATA-3 in the IL4 locus. The polarization of T-cell phenotypes involves a cross-regulation, where IL-4 inhibits the expression of the IFN-γ and vice versa.3Nakamura T. Kamogawa Y. Bottomly K. Flavell R.A. Polarization of IL-4- and IFN-gamma-producing CD4+ T cells following activation of naive CD4+ T cells.J Immunol. 1997; 158: 1085-1094PubMed Google Scholar TH1 commitment requires IFN-γ exposure to maintain the IL-12 receptor, and IL-4 inhibits the IL-12 receptor (R) β2.4Szabo S.J. Dighe A.S. Gubler U. Murphy K.M. Regulation of the interleukin (IL)-12R beta 2 subunit expression in developing T helper 1 (Th1) and Th2 cells.J Exp Med. 1997; 185: 817-824Crossref PubMed Scopus (876) Google Scholar This exclusive mechanism is also reflected by mechanisms of transcriptional regulation, where the TH1-lineage-decisive factor T-bet physically interacts and inhibits the TH2 factor GATA-3.5Hwang E.S. Szabo S.J. Schwartzberg P.L. Glimcher L.H. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3.Science. 2005; 307: 430-433Crossref PubMed Scopus (426) Google Scholar Because of the genetic imprinting, dividing cells will principally maintain the polarized phenotype throughout the process of clonal expansion. The TH2 cells are critically important for IgE induction, providing IL-4 and CD40-mediated interaction, which is necessary for the IgM to IgE switch reaction. In contrast, TH1 cells are important in macrophage activation and induction of MHC-II. Because of the mutual exclusiveness of TH1 and TH2, it was hypothesized that TH1 and TH2 cells are in a balance with each other and that allergies are characterized and caused by a dominance on the TH2 side of the equilibrium. This TH1/TH2 paradigm dominated allergy research and gave rise to the hygiene hypothesis, suggesting that increased hygiene conditions limit TH1 reactions, which in turn allows more TH2 reactions. The hygiene hypothesis was suggested to underlie increased allergy prevalence, although the increased prevalence of autoimmune disease was difficult to explain.6Bach J.F. The effect of infections on susceptibility to autoimmune and allergic diseases.N Engl J Med. 2002; 347: 911-920Crossref PubMed Scopus (2105) Google Scholar With the discovery of the T-regulatory (Treg) and the TH17 cells, this bivalent concept needs to be modified to integrate recent major progress in T-cell immunology and provide new access to epidemiologic dimensions of major immune system–related disease. The understanding of T-cell responses in allergy during the last decade not only highlighted the critical importance of TH2 cells in helping B cells toward IgE expression but also revealed that TH2 cells interact with other cells such as eosinophils via IL-5; smooth muscle cells via IL-9; epithelial cells and keratinocytes via IL-13; and epithelial cells via IL-31,7Dillon S.R. Sprecher C. Hammond A. 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Kemeny L. et al.IL-31: a new link between T cells and pruritus in atopic skin inflammation.J Allergy Clin Immunol. 2006; 117: 411-417Abstract Full Text Full Text PDF PubMed Scopus (753) Google Scholar Particular interest has been raised regarding the transition between allergen-driven IgE switch, which is mediated by IL-4 and IL-13 early in the disease process, and the airway remodeling observed on chronic allergen exposure, which has been attributed to the TH2 cytokine IL-13 and TGF-β expressed by Treg cells as well as many other tissue cells. Thus, TGF-β is playing an important role in the induction of extracellular matrix proteins in tissue repair, but it is only marginally induced in T cells on T-cell receptor (TCR) stimulation. In contrast, the allergen-inducible TGF-β family member activin, which stimulates TGF-β expression in structural cells, could be a mediator between acute exacerbations and chronic allergic inflammation.10Karagiannidis C. Hense G. Martin C. Epstein M. 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Apoptosis in tissue inflammation and allergic disease.Curr Opin Immunol. 2004; 16: 717-723Crossref PubMed Scopus (71) Google Scholar In addition, IL-21 was reported to be coexpressed with TH2 cytokines13Mehta D.S. Wurster A.L. Whitters M.J. Young D.A. Collins M. Grusby M.J. IL-21 induces the apoptosis of resting and activated primary B cells.J Immunol. 2003; 170: 4111-4118PubMed Google Scholar but to suppress IgE expression.14Harada M. Magara-Koyanagi K. Watarai H. Nagata Y. Ishii Y. Kojo S. et al.IL-21-induced Bepsilon cell apoptosis mediated by natural killer T cells suppresses IgE responses.J Exp Med. 2006; 203: 2929-2937Crossref PubMed Scopus (102) Google Scholar The IL-21R receptor was found on keratinocytes, suggesting that IL-21 could also contribute to tissue modulation. IL-31, not yet assigned to T-cell subsets, is also likely to play a role in allergy and is acting on epithelial cells and keratinocytes,7Dillon S.R. Sprecher C. Hammond A. Bilsborough J. Rosenfeld-Franklin M. 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However, TH17 cells could theoretically be of benefit to reduce matrix deposition, because TH17 cells, in contrast with TH2 cells, are capable of inducing metalloproteinases (Table I), which is an essential mechanism of TH17-mediated cartilage breakdown in arthritis and could be beneficial for remodelling in allergy.47Nakae S. Saijo S. Horai R. Sudo K. Mori S. Iwakura Y. IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist.Proc Natl Acad Sci U S A. 2003; 100: 5986-5990Crossref PubMed Scopus (417) Google Scholar, 52Lubberts E. Joosten L.A. van de Loo F.A. van den Gersselaar L.A. van den Berg W.B. 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