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• W2009283555 abstract "Asthma is a multifactorial disease of the airways characterized by airway inflammation, mucus hypersecretion, and airway hyperresponsiveness. Conventional MHC class II–restricted CD4+ T cells are considered a key cell in asthma pathogenesis because they have a broad T-cell receptor repertoire, providing specificity and reactivity to diverse protein allergens. This notion was challenged when a study found that invariant Natural Killer (NK) T cells were the predominant T cells in the lung and bronchoalveolar lavage fluid of all asthmatic subjects studied. This finding was provocative because invariant NKT cells have a very limited T-cell receptor repertoire and are specific for a restricted set of lipid antigens that bind to CD1d, a nonpolymorphic MHC-like molecule. However, multiple subsequent studies failed to replicate the initial study and instead found that invariant NKT cells are present as a small fraction of the total T cells in the asthmatic lung. Thus, we believe that although CD1d-restricted NKT cells might play a role in modulating the asthmatic phenotype, they are not the critical drivers of the asthmatic response, a role we believe is still held by conventional MHC class II–restricted CD4+ T cells. Asthma is a multifactorial disease of the airways characterized by airway inflammation, mucus hypersecretion, and airway hyperresponsiveness. Conventional MHC class II–restricted CD4+ T cells are considered a key cell in asthma pathogenesis because they have a broad T-cell receptor repertoire, providing specificity and reactivity to diverse protein allergens. This notion was challenged when a study found that invariant Natural Killer (NK) T cells were the predominant T cells in the lung and bronchoalveolar lavage fluid of all asthmatic subjects studied. This finding was provocative because invariant NKT cells have a very limited T-cell receptor repertoire and are specific for a restricted set of lipid antigens that bind to CD1d, a nonpolymorphic MHC-like molecule. However, multiple subsequent studies failed to replicate the initial study and instead found that invariant NKT cells are present as a small fraction of the total T cells in the asthmatic lung. Thus, we believe that although CD1d-restricted NKT cells might play a role in modulating the asthmatic phenotype, they are not the critical drivers of the asthmatic response, a role we believe is still held by conventional MHC class II–restricted CD4+ T cells. Invariant Natural Killer T (iNKT) cells burst onto the asthma scene in 2006 when the New England Journal of Medicine published a potentially paradigm-shifting article describing that iNKT cells and not conventional MHC class II–restricted CD4 T cells were the predominant T cells in the lungs and bronchoalveolar lavage (BAL) fluid of all patients studied with allergic asthma.1Akbari O. Faul J.L. Hoyte E.G. Berry G.J. Wahlstrom J. Kronenberg M. et al.CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354: 1117-1129Crossref PubMed Scopus (360) Google Scholar In the ensuing 4 years, the weight of evidence strongly suggests that iNKT cells are not the predominant T cells in the asthmatic lung and in fact represent a small fraction of T cells in the asthmatic lung.2Bratke K. Julius P. Virchow J.C. Invariant natural killer T cells in obstructive pulmonary diseases.N Engl J Med. 2007; 357: 194-195PubMed Google Scholar, 3Hamzaoui A. Cheik Rouhou S. Grairi H. Abid H. Ammar J. Chelbi H. et al.NKT cells in the induced sputum of severe asthmatics.Mediators Inflamm. 2006; 2006 (71214)Crossref PubMed Scopus (44) Google Scholar, 4Mutalithas K. Croudace J. Guillen C. Siddiqui S. Thickett D. Wardlaw A. et al.Bronchoalveolar lavage invariant natural killer T cells are not increased in asthma.J Allergy Clin Immunol. 2007; 119: 1274-1276Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 5Pham-Thi N. de Blic J. Leite-de-Moraes M.C. Invariant natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354: 2613-2616Crossref PubMed Scopus (48) Google Scholar, 6Thomas S.Y. Lilly C.M. Luster A.D. Invariant natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354: 2613-2616Crossref PubMed Scopus (68) Google Scholar, 7Vijayanand P. Seumois G. Pickard C. Powell R.M. Angco G. Sammut D. et al.Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease.N Engl J Med. 2007; 356: 1410-1422Crossref PubMed Scopus (175) Google Scholar This, coupled with the fact that iNKT cells have limited antigen specificity and reactivity to lipid and not protein antigens, leads us to believe that iNKT cells are not the major T cells that drive asthma pathogenesis and at most play a modulatory role. iNKT cells (also referred to as type I natural killer [NK] T cells) exhibit a very limited pattern of gene segment use in their T-cell antigen receptors. This is characterized by a semi-invariant T-cell receptor α chain rearrangement (Vα24-Jα18 in human subjects and Vα14-Jα18 in mice), which is most commonly paired with Vβ11 in human subjects8Porcelli S. Gerdes D. Fertig A.M. Balk S.P. Human T cells expressing an invariant V alpha 24-J alpha Q TCR alpha are CD4- and heterogeneous with respect to TCR beta expression.Hum Immunol. 1996; 48: 63-67Crossref PubMed Scopus (70) Google Scholar and with Vβ8.2, Vβ7, or Vβ2 in mice.9Lantz O. Bendelac A. An invariant T cell receptor alpha chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD4-8- T cells in mice and humans.J Exp Med. 1994; 180: 1097-1106Crossref PubMed Scopus (929) Google Scholar The limited diversity of T-cell receptors on iNKT cells is associated with a very narrow profile of antigenic specificity that is restricted to lipid antigen presented in the context of the β2-microglobulin–associated antigen-presenting molecule CD1d. Unlike the polymorphic MHC class I and II antigen-presenting molecules, which present peptide antigens to conventional CD8 and CD4 T cells, respectively, CD1d is nonpolymorphic and thus engages a more limited repertoire of CD1d-restricted NKT cells. These cells can be identified by means of their recognition of CD1d loaded with the nonphysiologic, glycolipid ligand α-galactosylceramide (α-GalCer) derived from sea sponges. There is also thought to be a more diverse pool of type II NKT cells that are restricted by CD1d but do not contain the canonical semi-invariant T-cell receptor rearrangement. Some of these CD1d-restricted diverse NKT cells can also respond to α-GalCer, but others are restricted to specific lipid antigens.10Bendelac A. Savage P.B. Teyton L. The biology of NKT cells.Annu Rev Immunol. 2007; 25: 297-336Crossref PubMed Scopus (1772) Google Scholar The identification of type II CD1d-restricted diverse NKT cells is technically complicated by the fact that individual lipid antigens must be characterized and loaded in CD1d tetramers to recognize and enumerate corresponding type II NKT cells. Type III NKT cells are not truly CD1d-restricted NKT cells but rather conventional T cells that express NK antigens, such as NK1.1 (CD161) and DX5 (CD49b) in the mouse or CD56 in human subjects. This is an important distinction because the term “type III NKT cells” has been inappropriately used to suggest that conventional T cells expressing NK-like markers are CD1d restricted or recognize lipid antigen. As mentioned above, type I iNKT cells have been identified in vivo by using CD1d tetramer loaded with a glycolipid derived from a marine sponge, α-GalCer, in both human subjects and mice. Although α-GalCer is neither an endogenous nor relevant exogenous glycolipid in mammals, type I iNKT cells bind and respond strongly to CD1d-mediated α-GalCer stimulation by rapidly producing a number of cytokines.11Kawano T. Cui J. Koezuka Y. Toura I. Kaneko Y. Motoki K. et al.CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides.Science. 1997; 278: 1626-1629Crossref PubMed Scopus (2149) Google Scholar In addition, human iNKT cells can be recognized by costaining with 6B11 and Vα24 antibodies, which recognize the semi-invariant rearrangement Vα24-Jα18. The 6B11 antibody was raised against the CDR3 loop of the Vα24-Jα18 rearrangement.12Exley M.A. Hou R. Shaulov A. Tonti E. Dellabona P. Casorati G. et al.Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR alpha-chain CDR3 loop.Eur J Immunol. 2008; 38: 1756-1766Crossref PubMed Scopus (75) Google Scholar, 13Montoya C.J. Pollard D. Martinson J. Kumari K. Wasserfall C. Mulder C.B. et al.Characterization of human invariant natural killer T subsets in health and disease using a novel invariant natural killer T cell-clonotypic monoclonal antibody, 6B11.Immunology. 2007; 122: 1-14Crossref PubMed Scopus (158) Google Scholar However, because this epitope can be also be expressed on non–CD1d-restricted T-cell receptors or B-cell receptors, it must be used in combination with Vα24 or Vβ11 antibodies to verify specific iNKT staining. Failure to use 6B11 in conjunction with Vα24 or Vβ11 antibodies can lead to an overestimate of the apparent number of iNKT cells in a specimen and has generated confusion in the literature. Care must be taken to also exclude nonspecific staining of tetramer, antibodies, or both to cells other than lymphocytes by means of appropriate gating in flow cytometric analysis, especially in BAL fluid samples that contain alveolar macrophages, which are notorious for being both highly autofluorescent and binding proteins nonspecifically.6Thomas S.Y. Lilly C.M. Luster A.D. Invariant natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354: 2613-2616Crossref PubMed Scopus (68) Google Scholar, 7Vijayanand P. Seumois G. Pickard C. Powell R.M. Angco G. Sammut D. et al.Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease.N Engl J Med. 2007; 356: 1410-1422Crossref PubMed Scopus (175) Google Scholar In fact, we and others believe that the large number of iNKT cells identified in the initial study by Umetsu's group1Akbari O. Faul J.L. Hoyte E.G. Berry G.J. Wahlstrom J. Kronenberg M. et al.CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354: 1117-1129Crossref PubMed Scopus (360) Google Scholar include alveolar macrophages rather than lymphocytes alone based on forward versus side scatter analysis in flow cytometry.6Thomas S.Y. Lilly C.M. Luster A.D. Invariant natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354: 2613-2616Crossref PubMed Scopus (68) Google Scholar, 7Vijayanand P. Seumois G. Pickard C. Powell R.M. Angco G. Sammut D. et al.Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease.N Engl J Med. 2007; 356: 1410-1422Crossref PubMed Scopus (175) Google Scholar CD1d-restricted iNKT cells are thought to respond to either self-glycolipid or phospholipid antigens or closely related bacterial glycolipid antigens. Several endogenous glycolipid or phospholipid antigens have been identified that can stimulate subsets of type I semi-invariant iNKT cells, type II diverse NKT cells, or both.10Bendelac A. Savage P.B. Teyton L. The biology of NKT cells.Annu Rev Immunol. 2007; 25: 297-336Crossref PubMed Scopus (1772) Google Scholar, 14Gumperz J.E. Roy C. Makowska A. Lum D. Sugita M. Podrebarac T. et al.Murine CD1d-restricted T cell recognition of cellular lipids.Immunity. 2000; 12: 211-221Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar, 15Fox L.M. Cox D.G. Lockridge J.L. Wang X. Chen X. Scharf L. et al.Recognition of lyso-phospholipids by human natural killer T lymphocytes.PLoS Biol. 2009; 7 (e1000228)Crossref PubMed Scopus (197) Google Scholar In addition to endogenous lipid stimulation of CD1d-restricted iNKT cells, exogenous glycolipids have been suggested to play a role in CD1d-restricted iNKT cell activation. Glycosphingolipids isolated from the cell wall of the gram-negative, LPS-negative bacterium Sphingomonas species have been shown to stimulate iNKT cells.16Kinjo Y. Wu D. Kim G. Xing G.W. Poles M.A. Ho D.D. et al.Recognition of bacterial glycosphingolipids by natural killer T cells.Nature. 2005; 434: 520-525Crossref PubMed Scopus (795) Google Scholar, 17Mattner J. Debord K.L. Ismail N. Goff R.D. Cantu 3rd, C. Zhou D. et al.Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections.Nature. 2005; 434: 525-529Crossref PubMed Scopus (950) Google ScholarSphingomonas species is an ubiquitous organism that can be easily aerosolized and stimulates an iNKT response.18Selmi C. Balkwill D.L. Invernizzi P. Ansari A.A. Coppel R.L. Podda M. et al.Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium.Hepatology. 2003; 38: 1250-1257Crossref PubMed Scopus (267) Google Scholar Other bacterial products, especially glycolipids from bacterial cell walls, also have the capacity to stimulate iNKT cells.19Tsuji M. Glycolipids and phospholipids as natural CD1d-binding NKT cell ligands.Cell Mol Life Sci. 2006; 63: 1889-1898Crossref PubMed Scopus (80) Google Scholar In addition, a glycolipid found in cedar pollen can stimulate iNKT cells.20Agea E. Russano A. Bistoni O. Mannucci R. Nicoletti I. Corazzi L. et al.Human CD1-restricted T cell recognition of lipids from pollens.J Exp Med. 2005; 202: 295-308Crossref PubMed Scopus (192) Google Scholar However, no other associations of specific lipid antigens capable of activating iNKT cells have been made with other allergens. Mechanistically, it seems implausible that lipid activation of iNKT cells is likely to do more than augment a protein allergen–driven MHC class II CD4 T-cell response, and even this has yet to be shown in human asthma. During bacterial infection, iNKT cells have been shown to be activated by the synergistic stimulation of self-lipids and proinflammatory cytokines.21Brigl M. Bry L. Kent S.C. Gumperz J.E. Brenner M.B. Mechanism of CD1d-restricted natural killer T cell activation during microbial infection.Nat Immunol. 2003; 4: 1230-1237Crossref PubMed Scopus (567) Google Scholar Although this has not been shown to occur in the asthmatic lung, it remains a possibility that iNKT cells could be activated by such a mechanism in asthma. However, this self-antigen hypothesis still suggests that another cell type would be responsible for producing the initial allergen-specific signal in patients with asthma and therefore favors the argument that iNKT cells play a modulatory and not primary role in asthma pathogenesis. iNKT cells were first suggested to play a critical role in the human asthmatic response in a 2006 New England Journal of Medicine study by the Umetsu group.1Akbari O. Faul J.L. Hoyte E.G. Berry G.J. Wahlstrom J. Kronenberg M. et al.CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354: 1117-1129Crossref PubMed Scopus (360) Google Scholar In that study CD1d-restricted iNKT cells were found to comprise more than 60% of CD3+ BAL T cells by means of flow cytometric analysis and a majority of CD4+ lymphocytes in asthmatic airway biopsy specimens by means of immunofluorescent histopathologic staining. Because CD1d-restricted iNKT cells generally make up less than 0.2% of human peripheral blood T cells, this would indeed be a greater than 300-fold increase in CD1d-restricted iNKT cells found in the BAL fluid compared with that seen in peripheral blood. We and all others2Bratke K. Julius P. Virchow J.C. Invariant natural killer T cells in obstructive pulmonary diseases.N Engl J Med. 2007; 357: 194-195PubMed Google Scholar, 3Hamzaoui A. Cheik Rouhou S. Grairi H. Abid H. Ammar J. Chelbi H. et al.NKT cells in the induced sputum of severe asthmatics.Mediators Inflamm. 2006; 2006 (71214)Crossref PubMed Scopus (44) Google Scholar, 4Mutalithas K. Croudace J. Guillen C. Siddiqui S. Thickett D. Wardlaw A. et al.Bronchoalveolar lavage invariant natural killer T cells are not increased in asthma.J Allergy Clin Immunol. 2007; 119: 1274-1276Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 5Pham-Thi N. de Blic J. Leite-de-Moraes M.C. Invariant natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354: 2613-2616Crossref PubMed Scopus (48) Google Scholar, 6Thomas S.Y. Lilly C.M. Luster A.D. Invariant natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354: 2613-2616Crossref PubMed Scopus (68) Google Scholar, 7Vijayanand P. Seumois G. Pickard C. Powell R.M. Angco G. Sammut D. et al.Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease.N Engl J Med. 2007; 356: 1410-1422Crossref PubMed Scopus (175) Google Scholar have observed significantly lower percentages of CD1d-restricted iNKT cells in the BAL fluid or sputum of human asthmatic subjects (<2.7% of CD3+ T cells) by means of flow cytometry with CD1d tetramers and the 6B11 antibody in combination with Vα24 or Vβ11 antibodies. This large discrepancy between the initial findings of the Umetsu group1Akbari O. Faul J.L. Hoyte E.G. Berry G.J. Wahlstrom J. Kronenberg M. et al.CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354: 1117-1129Crossref PubMed Scopus (360) Google Scholar and these other studies is likely accounted for by artifactually high staining in the original report caused by nonspecific binding of tetramer and antibodies to alveolar macrophages, which were not appropriately gated out in this original study.6Thomas S.Y. Lilly C.M. Luster A.D. Invariant natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354: 2613-2616Crossref PubMed Scopus (68) Google Scholar, 7Vijayanand P. Seumois G. Pickard C. Powell R.M. Angco G. Sammut D. et al.Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease.N Engl J Med. 2007; 356: 1410-1422Crossref PubMed Scopus (175) Google Scholar The significantly lower numbers of iNKT cells observed in later flow cytometric studies were confirmed by using a different method by Djukanovic's group, who also used quantitative (real-time) PCR to detect the mRNA for the genes of the T-cell receptor family, Vα24 or Vβ11, on BAL cells obtained from patients with asthma.7Vijayanand P. Seumois G. Pickard C. Powell R.M. Angco G. Sammut D. et al.Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease.N Engl J Med. 2007; 356: 1410-1422Crossref PubMed Scopus (175) Google Scholar BAL cells from subjects with asthma did not express mRNA for either the Vα24 or Vβ11 gene, even though mRNA for the constant chain of the T-cell receptor was readily detected. This finding confirmed the presence of T cells in the samples, but it also ruled out the possibility that iNKT cells were numerous in BAL fluid from subjects with asthma. In further experiments real-time PCR for mRNA expression of the iNKT cell receptor (Vβ11) relative to the expression of the constant chain of the T-cell receptor established that the proportion of T cells expressing T-cell receptor Vβ11-encoding mRNA was less than 2% in all samples obtained by means of BAL and sputum induction. A follow-up study by the Umetsu group22Matangkasombut P. Marigowda G. Ervine A. Idris L. Pichavant M. Kim H.Y. et al.Natural killer T cells in the lungs of patients with asthma.J Allergy Clin Immunol. 2009; 123: 1181-1185Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar in which the gating was now more appropriately performed failed to replicate their earlier study. Although an increase in CD1d-restricted iNKT cells in asthmatic subjects compared with nonasthmatic subjects was reported, the absolute magnitude of the percentage of iNKT cells in most of these patients was low and more than 10-fold less than the levels initially reported by this group.1Akbari O. Faul J.L. Hoyte E.G. Berry G.J. Wahlstrom J. Kronenberg M. et al.CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354: 1117-1129Crossref PubMed Scopus (360) Google Scholar Indeed, the percentage of iNKT cells among CD3+ T cells in the BAL fluid exceeded 10% in only a single patient. In contradistinction to the original report, this follow-up study22Matangkasombut P. Marigowda G. Ervine A. Idris L. Pichavant M. Kim H.Y. et al.Natural killer T cells in the lungs of patients with asthma.J Allergy Clin Immunol. 2009; 123: 1181-1185Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar and all other reported studies2Bratke K. Julius P. Virchow J.C. Invariant natural killer T cells in obstructive pulmonary diseases.N Engl J Med. 2007; 357: 194-195PubMed Google Scholar, 3Hamzaoui A. Cheik Rouhou S. Grairi H. Abid H. Ammar J. Chelbi H. et al.NKT cells in the induced sputum of severe asthmatics.Mediators Inflamm. 2006; 2006 (71214)Crossref PubMed Scopus (44) Google Scholar, 4Mutalithas K. Croudace J. Guillen C. Siddiqui S. Thickett D. Wardlaw A. et al.Bronchoalveolar lavage invariant natural killer T cells are not increased in asthma.J Allergy Clin Immunol. 2007; 119: 1274-1276Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 5Pham-Thi N. de Blic J. Leite-de-Moraes M.C. Invariant natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354: 2613-2616Crossref PubMed Scopus (48) Google Scholar, 6Thomas S.Y. Lilly C.M. Luster A.D. Invariant natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354: 2613-2616Crossref PubMed Scopus (68) Google Scholar, 7Vijayanand P. Seumois G. Pickard C. Powell R.M. Angco G. Sammut D. et al.Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease.N Engl J Med. 2007; 356: 1410-1422Crossref PubMed Scopus (175) Google Scholar agree that the vast majority of CD3+ T cells in the BAL fluid of asthmatic patients are therefore not iNKT cells. In this follow-up study, the Umetsu group22Matangkasombut P. Marigowda G. Ervine A. Idris L. Pichavant M. Kim H.Y. et al.Natural killer T cells in the lungs of patients with asthma.J Allergy Clin Immunol. 2009; 123: 1181-1185Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar also noted a trend toward an increase in percentages of iNKT cells in the lungs of patients with severe asthma compared with patients with well-controlled asthma. However, this observation failed to reach statistical significance, and moreover, this trend has not yet been observed by other investigators, making this an unsubstantiated hypothesis at present. In addition to studies examining BAL fluid and sputum for the presence of iNKT cells, several studies have examined bronchial biopsy specimens obtained from asthmatic patients for the presence of iNKT cells. The original study from the Umetsu group1Akbari O. Faul J.L. Hoyte E.G. Berry G.J. Wahlstrom J. Kronenberg M. et al.CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma.N Engl J Med. 2006; 354: 1117-1129Crossref PubMed Scopus (360) Google Scholar reporting an abundance of iNKT cells in the BAL fluid of asthmatic patients also noted that most CD4+ cells in the bronchial mucosa stained positive for the iNKT cell epitope 6B11. In this study the 6B11 antibody was used in histopathologic sections in conjunction with a CD4 antibody and not with a Vα24 chain antibody. Because CD4 is also expressed on macrophages, this might have led to an overestimation of the number of iNKT cells in the tissue. In fact, this finding was contradicted a year later by the results of Djukanovic's group.7Vijayanand P. Seumois G. Pickard C. Powell R.M. Angco G. Sammut D. et al.Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease.N Engl J Med. 2007; 356: 1410-1422Crossref PubMed Scopus (175) Google Scholar This study rigorously assessed the number of iNKT cells in bronchial biopsy specimens from asthmatic patients through multiple approaches, including staining with antibody against Vα24, CD1d tetramers loaded with α-GalCer, and the 6B11 mAb. Regardless of the staining method used, the counts of iNKT cells were very low and did not exceed 1.7% of the CD3+ T cells in the bronchial mucosa. Moreover, in this study the number of iNKT cells remained extremely low in patients with moderately severe asthma, as well as in patients with mild asthma, indicating that asthma severity did not affect the frequency of iNKT cells observed in the lung tissue. Thus the evidence in favor of a critical role of iNKT cells in human asthma remains limited to the demonstration that they are present in very low numbers in BAL fluid and bronchial biopsy specimens of patients with asthma, and to date, there is no association between iNKT cell numbers and a specific asthma phenotype. In contrast, there exists an abundance of evidence strongly implicating conventional MHC class II–restricted T-cell subsets in the pathogenesis of human asthma.23Robinson 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 Scopus (2560) Google Scholar, 24Gavett S.H. Chen X. Finkelman F. Wills-Karp M. Depletion of murine CD4+ T lymphocytes prevents antigen-induced airway hyperreactivity and pulmonary eosinophilia.Am J Respir Cell Mol Biol. 1994; 10: 587-593Crossref PubMed Scopus (453) Google Scholar, 25Walker C. Bode E. Boer L. Hansel T.T. Blaser K. Virchow Jr., J.C. Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage.Am Rev Respir Dis. 1992; 146: 109-115Crossref PubMed Scopus (713) Google Scholar, 26Cohn L. Homer R.J. Marinov A. Rankin J. Bottomly K. Induction of airway mucus production By T helper 2 (Th2) cells: a critical role for interleukin 4 in cell recruitment but not mucus production.J Exp Med. 1997; 186: 1737-1747Crossref PubMed Scopus (401) Google Scholar, 27Nakamura Y. Ghaffar O. Olivenstein R. Taha R.A. Soussi-Gounni A. Zhang D.H. et al.Gene expression of the GATA-3 transcription factor is increased in atopic asthma.J Allergy Clin Immunol. 1999; 103: 215-222Abstract Full Text Full Text PDF PubMed Google Scholar, 28Holgate S.T. Polosa R. Treatment strategies for allergy and asthma.Nat Rev Immunol. 2008; 8: 218-230Crossref PubMed Scopus (491) Google Scholar Because these cells represent a far greater percentage of CD3+ cells in the BAL fluid, it would be difficult at this time to conclude that iNKT cells play a more critical role in asthma than conventional T cells. The development of the allergic asthmatic response can be divided into sensitization, allergic inflammation, and exacerbation phases. Environmental antigens are constantly encountered in the airway during the breathing process, yet only selected agonists stimulate an allergic response. Airway antigen-presenting cells must distinguish between innocuous and potentially harmful stimuli, including viral and bacterial pathogens. Allergic asthma results from a dysregulation of the immune response to generate allergen-specific, rather than pathogen-specific, IgE and TH2 cells. The initial process of allergen sensitization likely begins with a combined encounter of allergen along with an adjuvant signal. Epithelial cells line the conducting airways, forming a barrier between inhaled antigens and mucosal dendritic cells (DCs).29Hammad H. Lambrecht B.N. Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma.Nat Rev Immunol. 2008; 8: 193-204Crossref PubMed Scopus (503) Google Scholar During the sensitization process, disruption of the epithelial cell layer can occur by means of intrinsic protease activity of certain allergens30Runswick S. Mitchell T. Davies P. Robinson C. Garrod D.R. Pollen proteolytic enzymes degrade tight junctions.Respirology. 2007; 12: 834-842Crossref PubMed Scopus (155) Google Scholar or increased vascular permeability through vascular endothelial growth factor induction,31Antony A.B. Tepper R.S. Mohammed K.A. Cockroach extract antigen increases bronchial airway epithelial permeability.J Allergy Clin Immunol. 2002; 110: 589-595Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar as well as through environmental factors, such as smoking32Olivera D.S. Boggs S.E. Beenhouwer C. Aden J. Knall C. Cellular mechanisms of mainstream cigarette smoke-induced lung epithelial tight junction permeability changes in vitro.Inhal Toxicol. 2007; 19: 13-22Crossref PubMed Scopus (93) Google Scholar and ozone exposure.33Broeckaert F. Arsalane K. Hermans C. Bergamaschi E. Brustolin A. Mutti A. et al.Serum clara cell protein: a sensitive biomarker of increased lung epithelium permeability caused by ambient ozone.Environ Health Perspect. 2000; 108: 533-537Crossref PubMed Scopus (104) Google Scholar In conjunction with adjuvant signals from pattern-recognition receptors and protease-activated receptors, epithelial cells are triggered to produce thymic stromal lymphopoietin and GM-CSF, which aid in the maturation and polarization of airway DCs toward a TH2-promoting phenotype. iNKT cells could facilitate sensitization in the initial allergic asthmatic response with endogenous or exogenous lipid antigen as an adjuvant in place of or together with pattern-recognition receptors on DCs. After sensitization to an allergen, triggering of the allergic asthmatic response is initiated by means of re-exposure to the allergen and binding of the antigen to preformed IgE antibodies. The early allergic response is initiated by cross-linking of allergen-specific IgE on mast cells, leading to mast cell degranulation and release of inflammatory mediators, including histamine, leukotrienes, and prostaglandins, as well as both inflammatory and TH2-associated cytokines and chemokines.34Medoff B.D. Thomas S.Y. Luster A.D. T cell trafficking in alle" @default.
• W2009283555 created "2016-06-24" @default.
• W2009283555 creator A5044747238 @default.
• W2009283555 creator A5055995920 @default.
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• W2009283555 date "2010-05-01" @default.
• W2009283555 modified "2023-10-02" @default.
• W2009283555 title "Natural killer T cells are not the predominant T cell in asthma and likely modulate, not cause, asthma" @default.
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