The role of the T cell in asthma
2010; Elsevier BV; Volume: 126; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2010.06.025
ISSN1097-6825
Autores Tópico(s)Immune Cell Function and Interaction
ResumoSince the initial detection of TH2 cytokines in asthmatic airways, our understanding of the complexity of T-cell subtypes and flexibility and of the potential role of airway structural cells in the immunopathology of asthma has increased. Cytokines derived from airway epithelium, including IL-25, IL-33, and thymic stromal lymphopoietin, might be important drivers of TH2-type inflammation in asthma. The balance between effector TH2 cells and suppressive regulatory T cells is skewed toward a proinflammatory TH2 response in atopy and asthma, and there is much interest in how to redress this equilibrium. Novel T-cell subsets, including TH17, TH9, and TH22, have been described, although their role in asthma remains unclear. Other T cells, including natural killer T cells, γδ T cells, and CD8 T cells, have also been implicated in asthma, although their importance remains to be confirmed. Therapeutic strategies aimed at TH2 cytokines are beginning to bear fruit in patients with asthma, although like many biologic agents, these might need specific targeting at subgroups of patients. Strategies directed specifically at the T cells are currently being evaluated, including novel forms of allergen immunotherapy. T cells remain an exciting potential target for new treatments in patients with asthma. Since the initial detection of TH2 cytokines in asthmatic airways, our understanding of the complexity of T-cell subtypes and flexibility and of the potential role of airway structural cells in the immunopathology of asthma has increased. Cytokines derived from airway epithelium, including IL-25, IL-33, and thymic stromal lymphopoietin, might be important drivers of TH2-type inflammation in asthma. The balance between effector TH2 cells and suppressive regulatory T cells is skewed toward a proinflammatory TH2 response in atopy and asthma, and there is much interest in how to redress this equilibrium. Novel T-cell subsets, including TH17, TH9, and TH22, have been described, although their role in asthma remains unclear. Other T cells, including natural killer T cells, γδ T cells, and CD8 T cells, have also been implicated in asthma, although their importance remains to be confirmed. Therapeutic strategies aimed at TH2 cytokines are beginning to bear fruit in patients with asthma, although like many biologic agents, these might need specific targeting at subgroups of patients. Strategies directed specifically at the T cells are currently being evaluated, including novel forms of allergen immunotherapy. T cells remain an exciting potential target for new treatments in patients with asthma. 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: December 2010. Credit may be obtained for these courses until November 30, 2012.Copyright Statement: Copyright © 2010-2012. 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: Douglas S. Robinson, MD, FRCPActivity Objectives1.To understand the variants of differentiated T cells, their role in asthma, and their respective cytokines in the pathogenesis of asthma.2.To identify cytokines important in asthma and eosinophilic bronchitis.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: D. S. Robinson is employed by Leti Laboratories; is a consultant for MedImmune, Inc; and is a research investigator for Imperial College.It is now more than 20 years since the seminal description by Mosmann et al1Mosmann T.R. Cherwinski H. Bond M.W. Giedlin M.A. Coffman R.L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.J Immunol. 1986; 136: 2348-2357PubMed Google Scholar of 2 functional subsets of murine TH clones termed TH1 and TH2. It has been almost 20 years since our group, among others, published evidence that atopic asthma was associated with activation of a TH2 type of T cell in the airway.2Robinson D.S. Hamid Q. Ying S. Tsicopoulos A. Barkans J. Bentley A.M. et al.Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma.N Engl J Med. 1992; 326: 298-304Crossref PubMed Google Scholar Expression of TH2 cytokines could be related to activity of disease, symptom scores, airway eosinophilia, and bronchial hyperresponsiveness3Robinson D.S. Ying S. Bentley A.M. Meng Q. North J. Durham S.R. et al.Relationships among numbers of bronchoalveolar lavage cells expressing messenger ribonucleic acid for cytokines, asthma symptoms, and airway methacholine responsiveness in atopic asthma.J Allergy Clin Immunol. 1993; 92: 397-403Abstract Full Text PDF PubMed Scopus (205) Google Scholar; increased after allergen challenge4Robinson D. Hamid Q. Bentley A. Ying S. Kay A.B. Durham S.R. Activation of CD4+ T cells, increased TH2-type cytokine mRNA expression, and eosinophil recruitment in bronchoalveolar lavage after allergen inhalation challenge in patients with atopic asthma.J Allergy Clin Immunol. 1993; 92: 313-324Abstract Full Text PDF PubMed Google Scholar; and decreased with corticosteroid treatment of asthma.5Robinson D. Hamid Q. Ying S. Bentley A. Assoufi B. Durham S. et al.Prednisolone treatment in asthma is associated with modulation of bronchoalveolar lavage cell interleukin-4, interleukin-5, and interferon-gamma cytokine gene expression.Am Rev Respir Dis. 1993; 148: 401-406Crossref PubMed Google Scholar Additional clinical studies, genetic studies, and many studies of animal models of allergic airways disease have supported the TH2 hypothesis of asthma, namely that allergen-specific TH2 cells drive many of the immunopathologic features of asthma (Fig 1). In addition, a TH2 cytokine profile was also demonstrated in patients with nonatopic asthma.6Humbert M. Durham S.R. Ying S. Kimmitt P. Barkans J. Assoufi B. et al.IL-4 and IL-5 mRNA and protein in bronchial biopsies from patients with atopic and nonatopic asthma: evidence against "intrinsic" asthma being a distinct immunopathologic entity.Am J Respir Crit Care Med. 1996; 154: 1497-1504Crossref PubMed Google ScholarAs further studies reveal the heterogeneity of asthma phenotypes and response to treatment, the complexity of the immunology of both T cells and asthma, and the contribution of structural airway tissue cells to pathophysiology, it has become fashionable to question the relevance of the TH2 hypothesis. Therefore where does the TH2 hypothesis of asthma stand today, and what is the current understanding of the role of T cells in asthma?Defining and understanding the heterogeneity of asthmaInitial studies of T cells in asthma were performed when classification of subtypes of asthma went little further than separating out atopic allergic disease from nonatopic or intrinsic asthma, with possible overlapping subgroups of occupational and aspirin-sensitive asthma. By means of analysis of cytokine gene expression and airway inflammation, these subtypes appeared similar, with eosinophilic inflammation and TH2 cytokines prominent. Indeed, detection of local airway IgE synthesis, together with identification of autoallergens, raises the possibility that nonatopic asthma might be a form of autoallergy with a TH2 response to self-antigens. Autoallergens is a term suggested for self-antigens recognized by IgE, such as Hom s 1.7Valenta R. Seiberler S. Natter S. Mahler V. Mossabeb R. Ring J. et al.Autoallergy: a pathogenetic factor in atopic dermatitis?.J Allergy Clin Immunol. 2000; 105: 432-437Abstract Full Text Full Text PDF PubMed Google Scholar Thus the concept arose of a unifying TH2-type inflammation in all forms of asthma, providing an attractive rationale for TH2-targeted therapy.A series of investigations of asthma's immunopathology have focused on comparison of asthma with eosinophilic bronchitis (EB).8Gibson P.G. Dolovich J. Denburg J. Ramsdale E.H. Hargreave F.E. Chronic cough: eosinophilic bronchitis without asthma.Lancet. 1989; 1: 1346-1348Abstract PubMed Google Scholar, 9Brightling C.E. Bradding P. Symon F.A. Holgate S.T. Wardlaw A.J. Pavord I.D. Mast-cell infiltration of airway smooth muscle in asthma.N Engl J Med. 2002; 346: 1699-1705Crossref PubMed Scopus (729) Google Scholar, 10Brightling C.E. Symon F.A. Birring S.S. Bradding P. Pavord I.D. Wardlaw A.J. TH2 cytokine expression in bronchoalveolar lavage fluid T lymphocytes and bronchial submucosa is a feature of asthma and eosinophilic bronchitis.J Allergy Clin Immunol. 2002; 110: 899-905Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 11Berry M.A. Parker D. Neale N. Woodman L. Morgan A. Monk P. et al.Sputum and bronchial submucosal IL-13 expression in asthma and eosinophilic bronchitis.J Allergy Clin Immunol. 2004; 114: 1106-1109Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar EB was initially characterized by Gibson et al8Gibson P.G. Dolovich J. Denburg J. Ramsdale E.H. Hargreave F.E. Chronic cough: eosinophilic bronchitis without asthma.Lancet. 1989; 1: 1346-1348Abstract PubMed Google Scholar as eosinophilic airway inflammation (detected in sputum eosinophilia) with cough but no other physiological features of asthma, such as airway obstruction or hyperreactivity. The group in Leicester, United Kingdom, have shown that EB and asthma share many of what were previously thought to be cardinal features of asthma, including eosinophilic inflammation and features of airway remodeling. The distinguishing immunopathologic feature between EB and asthma was infiltration of mast cells into the airway smooth muscle in patients with asthma, which was not seen in patients with EB.9Brightling C.E. Bradding P. Symon F.A. Holgate S.T. Wardlaw A.J. Pavord I.D. Mast-cell infiltration of airway smooth muscle in asthma.N Engl J Med. 2002; 346: 1699-1705Crossref PubMed Scopus (729) Google Scholar Analysis of bronchoalveolar lavage T cells by means of intracellular cytokine staining showed higher percentages of CD4+ T cells staining for IL-4 in both patients with EB (7.2%) and those with asthma (5.3%) than in control volunteers (2.8%), whereas IFN-γ–producing T cells were not different in numbers among the 3 groups.10Brightling C.E. Symon F.A. Birring S.S. Bradding P. Pavord I.D. Wardlaw A.J. TH2 cytokine expression in bronchoalveolar lavage fluid T lymphocytes and bronchial submucosa is a feature of asthma and eosinophilic bronchitis.J Allergy Clin Immunol. 2002; 110: 899-905Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar By means of immunohistology, IL-4+ and IL-5+ cells were increased in both patients with EB and those with asthma, although these were mostly non-T cells. IL-13 levels were increased in the bronchial mucosa in patients with asthma compared with those seen in patients with EB but was mostly localized to eosinophils by using the staining techniques used.11Berry M.A. Parker D. Neale N. Woodman L. Morgan A. Monk P. et al.Sputum and bronchial submucosal IL-13 expression in asthma and eosinophilic bronchitis.J Allergy Clin Immunol. 2004; 114: 1106-1109Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar Thus these studies suggest that TH2 T cells might contribute to many of the immunopathologic features of asthma, but because these are also seen in patients with EB, other factors must act in concert with TH2 cells to produce the characteristic pathophysiology of asthma or act to prevent asthma in patients with EB. Further studies of patients with EB and asthma will be of interest.Recent studies have aimed to subtype asthma by using a cluster analysis of multiple variables measured in large cohorts with differing disease severities.12Haldar P. Pavord I.D. Shaw D.E. Berry M.A. Thomas M. Brightling C.E. et al.Cluster analysis and clinical asthma phenotypes.Am J Respir Crit Care Med. 2008; 178: 218-224Crossref PubMed Scopus (486) Google Scholar, 13Moore W.C. Meyers D.A. Wenzel S.E. Teague W.G. Li H. Li X. et al.Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program.Am J Respir Crit Care Med. 2010; 181: 315-323Crossref PubMed Scopus (416) Google Scholar The aim here is to perform an unbiased analysis to examine how these variables cluster to define subgroups rather than predefine types of asthma. Clearly an important first step is to confirm the diagnosis of asthma and consider adherence with treatment.14Heaney L.G. Robinson D.S. Severe asthma treatment: need for characterising patients.Lancet. 2005; 365: 974-976Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar Two large studies have shown broadly similar clusters, including a large group with early-onset atopic asthma (which can be subdivided by response to treatment), a cluster of female subjects with older-onset nonatopic asthma, a cluster of patients who have persistent eosinophilic disease as detected by sputum eosinophilia but few symptoms, and a subgroup with persistent symptoms but relatively little airway inflammation.12Haldar P. Pavord I.D. Shaw D.E. Berry M.A. Thomas M. Brightling C.E. et al.Cluster analysis and clinical asthma phenotypes.Am J Respir Crit Care Med. 2008; 178: 218-224Crossref PubMed Scopus (486) Google Scholar, 13Moore W.C. Meyers D.A. Wenzel S.E. Teague W.G. Li H. Li X. et al.Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program.Am J Respir Crit Care Med. 2010; 181: 315-323Crossref PubMed Scopus (416) Google Scholar Defining these subgroups within severe asthma cohorts will be particularly important for targeting immunologically based therapy (see below).15Levine S.J. Wenzel S.E. Narrative review: the role of Th2 immune pathway modulation in the treatment of severe asthma and its phenotypes.Ann Intern Med. 2010; 152: 232-237Crossref PubMed Google Scholar In addition, a small percentage of subjects with severe asthma have steroid-resistant asthma and do not respond well to inhaled or oral steroid treatment. It is not yet clear how these different clusters fit within the TH2 hypothesis of asthma: response to anticytokine treatment (considered below) suggests there might be subgroups of patients with severe asthma in which eosinophilia is relevant, particularly to asthma exacerbations, despite corticosteroid therapy, whereas other factors, as yet less well defined, might play a role in clusters with persistent symptoms without much airway inflammation. Are other types of T cells involved in some of these subtypes? Let us first consider the increasing complexity of T cells and cytokines that might play a role in asthma.T-cell complexity and flexibilitySince the initial description of TH1 and TH2 cells, an increasing array of cytokines and chemokines has been described, both produced by and influencing differentiation of TH1 and TH2 cells. In addition, new proinflammatory and suppressive (or regulatory) T-cell subsets have been defined, and our understanding of T-cell programming and flexibility has increased at the level of the transcription factors acting to augment or repress cytokines genes and the resulting epigenetic changes involved in determining the stability of TH cell phenotypes. How does this increased knowledge affect our understanding of asthma?CytokinesIn addition to the canonical TH2 cytokines IL-4 and IL-5, additional cytokines relevant to asthma have been described. In particular, IL-13, which is clustered with il4, il5, and gm-csf genes on chromosome 5q and is coordinately expressed with IL-4 and IL-5 in murine and human TH2 cells,16Locksley R.M. Nine lives: plasticity among T helper cell subsets.J Exp Med. 2009; 206: 1643-1646Crossref PubMed Scopus (60) Google Scholar, 17Cousins D.J. Lee T.H. Staynov D.Z. Cytokine coexpression during human Th1/Th2 cell differentiation: direct evidence for coordinated expression of Th2 cytokines.J Immunol. 2002; 169: 2498-2506Crossref PubMed Google Scholar is of great current interest. First, studies of mRNA and protein expression showed increased IL-13 levels in the airways in both patients with atopic and those with nonatopic asthma, with preferential expression of IL-13 in airway eosinophils and blood T cells from asthmatic patients when compared with patients with EB.11Berry M.A. Parker D. Neale N. Woodman L. Morgan A. Monk P. et al.Sputum and bronchial submucosal IL-13 expression in asthma and eosinophilic bronchitis.J Allergy Clin Immunol. 2004; 114: 1106-1109Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 18Humbert M. Durham S.R. Kimmitt P. Powell N. Assoufi B. Pfister R. et al.Elevated expression of messenger ribonucleic acid encoding IL-13 in the bronchial mucosa of atopic and nonatopic subjects with asthma.J Allergy Clin Immunol. 1997; 99: 657-665Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar Second, the biology of IL-13 makes it another clear candidate for driving features of asthma: it shares activity with IL-4 in switching B cells to IgE production and activating monocytes and macrophages and increases airway mucus production through goblet cell hyperplasia.19Wills-Karp M. Interleukin-13 in asthma pathogenesis.Immunol Rev. 2004; 202: 175-190Crossref PubMed Scopus (360) Google Scholar IL-13 shares a receptor with IL-4 and has its own IL-13 receptor α chain, which is not expressed by naive T cells. Hence IL-13 (unlike IL-4) does not drive TH2 differentiation. Blocking the IL-13 receptor α chain (with a fusion protein that also blocked the IL-4 receptor α chain) dramatically reduced airway hyperresponsiveness in a murine model of allergic airways disease and interestingly did so without affecting either airway eosinophil infiltration or allergen-specific IgE.20Wills-Karp M. Luyimbazi J. Xu X. Schofield B. Neben T.Y. Karp C.L. et al.Interleukin-13: central mediator of allergic asthma.Science. 1998; 282: 2258-2261Crossref PubMed Scopus (1798) Google Scholar Initial results with agents that block the IL-13 receptor in clinical trials are mixed.21Wenzel S. Wilbraham D. Fuller R. Getz E.B. Longphre M. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies.Lancet. 2007; 370: 1422-1431Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar, 22Corren J. Busse W. Meltzer E.O. Mansfield L. Bensch G. Fahrenholz J. et al.A randomized, controlled, phase 2 study of AMG 317, an IL-4Rα antagonist, in patients with asthma.Am J Respir Crit Care Med. 2010; 181: 788-796Crossref PubMed Scopus (133) Google ScholarIL-6 is produced by TH2 cells (as well as many other cells types, including airway epithelium), and in addition to being an acute-phase proinflammatory cytokine, it is implicated in enhancing TH2 differentiation and proliferation of memory TH2 cells. In addition, IL-6 inhibits suppression by CD4+CD25+ regulatory T (Treg) cells.23Pasare C. Medzhitov R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells.Science. 2003; 299: 1033-1036Crossref PubMed Scopus (1468) Google Scholar In a murine model blockade of the soluble IL-6 receptor α chain reduced airway inflammation, whereas blockade of membrane-bound IL-6 receptor α chain increased Treg cell numbers.24Doganci A. Eigenbrod T. Krug N. De Sanctis G.T. Hausding M. Erpenbeck V.J. et al.The IL-6R alpha chain controls lung CD4+CD25+ Treg development and function during allergic airway inflammation in vivo.J Clin Invest. 2005; 115: 313-325Crossref PubMed Scopus (230) Google Scholar Unless targeted to the airway blocking, IL-6 might adversely affect the ability to mount acute-phase responses.IL-9 is a TH2 cytokine that is also a current drug target (antibodies are in phase II development). It acts to enhance TH2 cytokine production, airway mucus production, and eosinophil and basophil differentiation among other actions, at least in part by induction of IL-13 production.25Steenwinckel V. Louahed J. Orabona C. Huaux F. Warnier G. McKenzie A. et al.IL-13 mediates in vivo IL-9 activities on lung epithelial cells but not on hematopoietic cells.J Immunol. 2007; 178: 3244-3251Crossref PubMed Google Scholar In murine models blockade of IL-9 reduced airways hyperresponsiveness (AHR) and airway mast cell numbers. IL-9 has been linked to asthma in genetic studies, and its expression is increased in the airways of asthmatic patients.26Shimbara A. Christodoulopoulos P. Soussi-Gounni A. Olivenstein R. Nakamura Y. Levitt R.C. et al.IL-9 and its receptor in allergic and nonallergic lung disease: increased expression in asthma.J Allergy Clin Immunol. 2000; 105: 108-115Abstract Full Text Full Text PDF PubMed Google Scholar Recent reports of TH9 cells raise the question of whether IL-9 might be produced by these cells in asthma (see below).IL-31 is a member of the IL-6 cytokine family also produced by TH2 cells. Although it has principally been linked to atopic dermatitis, increased expression was detected in airway tissues from sensitized mice after allergen challenge, and serum IL-31 concentrations were increased in asthmatic patients, as were IL-31 transcripts in PBMCs.27Dillon S.R. Sprecher C. Hammond A. Bilsborough J. Rosenfeld-Franklin M. Presnell S.R. et al.Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice.Nat Immunol. 2004; 5: 752-760Crossref PubMed Scopus (313) Google Scholar, 28Lei Z. Liu G. Huang Q. Lv M. Zu R. Zhang G.M. et al.SCF and IL-31 rather than IL-17 and BAFF are potential indicators in patients with allergic asthma.Allergy. 2008; 63: 327-332Crossref PubMed Scopus (33) Google Scholar How IL-31 might act in patients with asthma is unclear, although it might affect epithelial cell functions, and intervention studies are not yet reported in mice or human subjects.Increasingly, the interplay between tissues and the adaptive immune system is recognized as an important factor in inflammation, including asthma. A group of cytokines derived from a variety of cell types might act in initiating, amplifying, and maintaining TH2-type inflammation in patients with asthma. These include thymic stromal lymphopoietin (TSLP), IL-25, IL-33, and osteopontin.29Saenz S.A. Taylor B.C. Artis D. Welcome to the neighborhood: epithelial cell-derived cytokines license innate and adaptive immune responses at mucosal sites.Immunol Rev. 2008; 226: 172-190Crossref PubMed Scopus (177) Google Scholar, 30Xanthou G. Alissafi T. Semitekolou M. Simoes D.C. Economidou E. Gaga M. et al.Osteopontin has a crucial role in allergic airway disease through regulation of dendritic cell subsets.Nat Med. 2007; 13: 570-578Crossref PubMed Scopus (95) Google Scholar TSLP, which is related to IL-7 and derived from epithelial cells in response to infectious agents, damage, and allergens, acts on dendritic cells to upregulate surface OX40 ligand and hence favors TH2 differentiation. It also directly activates mast cells. TSLP expression is increased in the airways in asthma, and blocking TSLP can reduce inflammation and AHR in murine models.31Liu Y.J. Thymic stromal lymphopoietin and OX40 ligand pathway in the initiation of dendritic cell-mediated allergic inflammation.J Allergy Clin Immunol. 2007; 120: 238-244Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar IL-25 was initially described as a murine TH2 cell product and can be produced by mast cells and epithelial cells, but in human patients with asthma, it appears to be produced predominantly by eosinophils and basophils.32Wang Y.H. Angkasekwinai P. Lu N. Voo K.S. Arima K. Hanabuchi S. et al.IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells.J Exp Med. 2007; 204: 1837-1847Crossref PubMed Scopus (262) Google Scholar Murine epithelial cells produced IL-25 in response to allergen exposure.33Angkasekwinai P. Park H. Wang Y.H. Wang Y.H. Chang S.H. Corry D.B. et al.Interleukin 25 promotes the initiation of proallergic type 2 responses.J Exp Med. 2007; 204: 1509-1517Crossref PubMed Scopus (245) Google Scholar Instillation or overexpression of IL-25 in the airways of mice caused TH2-type inflammation and AHR, and blockade of IL-25 at both the sensitization and challenge phases reduced inflammation and AHR in a murine allergic airways model.32Wang Y.H. Angkasekwinai P. Lu N. Voo K.S. Arima K. Hanabuchi S. et al.IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells.J Exp Med. 2007; 204: 1837-1847Crossref PubMed Scopus (262) Google Scholar IL-25 acted on human memory TH2 cells to increase GATA-3 and c-maf expression and thus increased cell numbers and cytokine production.32Wang Y.H. Angkasekwinai P. Lu N. Voo K.S. Arima K. Hanabuchi S. et al.IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells.J Exp Med. 2007; 204: 1837-1847Crossref PubMed Scopus (262) Google Scholar In the initial article describing IL-25, it was shown that it still induces TH2 cytokines in mice lacking T cells, raising the possibility of a T cell–independent pathway for TH2-type cytokine production.34Hurst S.D. Muchamuel T. Gorman D.M. Gilbert J.M. Clifford T. Kwan S. et al.New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25.J Immunol. 2002; 169: 443-453Crossref PubMed Google Scholar More recently, IL-25 has been shown to induce TH2 cytokine production from hematopoietic lineage cells recently identified as multipotent progenitors and a linage termed nuocytes35Neill D.R. Wong S.H. Bellosi A. Flynn R.J. Daly M. Langford T.K. et al.Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity.Nature. 2010; 464: 1367-1370Crossref PubMed Scopus (491) Google Scholar, 36Saenz S.A. Siracusa M.C. Perrigoue J.G. Spencer S.P. Urban Jr., J.F. Tocker J.E. et al.IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses.Nature. 2010; 464: 1362-1366Crossref PubMed Scopus (260) Google Scholar: whether this action amplifies airway inflammation in asthma or acts independently of T-cell activation is as yet unknown.IL-33 is an IL-1 family cytokine that acts to increase cytokine production from polarized TH2 cells (through the receptor termed T1/ST2) in a manner analogous to the IL-1 family member IL-18, which enhances cytokine production from polarized TH1 cells.29Saenz S.A. Taylor B.C. Artis D. Welcome to the neighborhood: epithelial cell-derived cytokines license innate and adaptive immune responses at mucosal sites.Immunol Rev. 2008; 226: 172-190Crossref PubMed Scopus (177) Google Scholar Neither cytokine acts on naive T cells. Unlike other IL-1 family members, IL-33 does not require caspase activation. Indeed, caspases from apoptotic cells acted to reduce its activity.37Lüthi A.U. Cullen S.P. McNeela E.A. Duriez P.J. Afonina I.S. Sheridan C. et al.Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases.Immunity. 2009; 31: 84-98Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar IL-33 is produced by airway epithelial cells, fibroblasts, and smooth muscle cells and therefore might also act as link between tissue cells and the adaptive immune response in asthma. Recently, IL-33 was reported to act on murine bone marrow–derived dendritic cells to induce a dendritic cell phenotype that activated IL-5 and IL-13, but not IL-4 or IFN-γ, production from naive CD4+ T cells.38Rank M.A. Kobayashi T. Kozaki H. Bartemes K.R. Squillace D.L. Kita H. IL-33-activated dendritic cells induce an atypical TH2-type response.J Allergy Clin Immunol. 2009; 123: 1047-1054Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar Whether this is relevant to human asthma remains unclear. IL-33 also acts on mast cells and basophils to increase survival and cytokine production and on eosinophils to prime for degranulation. IL-33 expression was increased in the airways of patients with severe asthma.39Préfontaine D. Lajoie-Kadoch S. Foley S. Audusseau S. Olivenstein R. Halayko A.J. et al.Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells.J Immunol. 2009; 183: 5094-5103Crossref PubMed Scopus (158) Google Scholar What activates IL-33 production from airway epithelium in asthmatic patients remains to be determined. Both IL-33 and IL-25 induce TSLP production from epithelial cells.29Saenz S.A. Taylor B.C. Artis D. Welcome to the neighborhood: epithelial cell-derived cytokines license innate and adaptive immune responses at mucosal sites.Immunol Rev. 2008; 226: 172-190Crossref PubMed Scopus (177) Google Scholar This triad of cytokines might represent a potential target for intervention in asthma and a way of intervening in epithelial cell–T-cell cross-talk.Osteopontin is produced from a variety
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