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Natural killer T cells in pulmonary disorders
Respiratory Medicine (2011) 105 S1, S20–S25
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/rmed
Natural killer T cells in pulmonary disorders Matija Rijaveca , Sinisa Volarevicb , Katarina Osolnika , Mitja Kosnika , Peter Koroseca a b
University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia Department of Molecular Medicine and Biotechnology, School of Medicine, University of Rijeka, Croatia
KEYWORDS Asthma; COPD; Hypersensitivity; Lung cancer; NKT cells; Pneumonitis; Sarcoidosis; Tuberculosis
Summary Natural killer T (NKT) cells, a unique subgroup of lymphocytes with features of both T and natural killer (NK) cells, represent a bridge between innate and adaptive immunity. They have the ability to either promote or suppress immune responses. With these immunoregulatory functions, NKT cells have emerged as an important subset of lymphocytes with a protective role in some disorders, such as infections, cancer, and possibly sarcoidosis, and a pathogenic role in others, such as asthma, chronic obstructive pulmonary disease and hypersensitivity pneumonitis. Immunotherapeutic interventions to modulate the immune response by targeting iNKT cell functions has become a challenging field and has shown promising results for the development of new therapies. © 2011 Elsevier Ltd. All rights reserved.
NKT cell heterogeneity Natural killer T (NKT) cells and NKT-like cells comprise a unique, yet highly heterogeneous subgroup of lymphocytes that express features of both T cells and natural killer (NK) cells and coexpress T-cell receptors (TCRs) together with markers associated with NK cells, such as CD56 and/or CD161.1–3 These cells are phenotypically and functionally highly diverse, but all are hybrid by nature and represent a bridge between innate and adaptive immunity (Table 1). Along with macrophages, dendritic cells, and others, NK cells are part of the innate immune system, whereas the acquired immune system is defined by the clonal expansion of antigen-specific T and B cells and their memory immune responses. Because NKT and NKT-like cells are part of both systems, their absence, depletion, or improper function affects both innate and acquired immunity.1–4
Type I and Type II NKT cells In humans there are two major subsets of NKT cells that are dependent on the presentation of the antigen through CD1d, a nonpolymorphic class I antigen-presenting molecule. CD1d is expressed on many different cells, including dendritic * Corresponding author. Matija Rijavec. University Clinic of Respiratory and Allergic Diseases, Golnik 36, 4204 Golnik, Slovenia. E-mail: [email protected] (M. Rijavec).
cells, thymocytes, B cells, monocytes, and macrophages. When glycolipid antigen binds to CD1d, the antigen/CD1d complex binds to the TCR of NKT cells.2,5 The most widely studied are CD1d-dependent cells, which express a highly restricted TCR with an invariant Va24-Ja18 preferentially paired with Vb11. These are called invariant NKT (iNKT) cells or type I NKT cells.1,2,4,6 The best-known iNKT cell antigen is the glycolipid a-galactosylceramide (a-GalCer), originally isolated from the marine sponge Agelas mauritianus, which is also used to identify cells as a-GalCer-loaded CD1d tetramers.1,7 Other glycolipid antigens for iNKT cells have been identified, including bacterial glycolipids such as a-galacturonosylceramide, a-glucuronosylceramide, and a-galactosyl-diacylglycerol, as well as mammalian glycolipids such as isoglobotrihexosylceramide (iGb3) and the disialoganglioside GD3.2,8,9 Activated iNKT cells rapidly release large amounts of both T-helper 1 (TH 1), TH 2, and/or TH 17-specific cytokines and exhibit both antigen-specific and NK-like cytolytic activities.1,2,5,10 Invariant NKT cells are therefore able to both promote and suppress immune responses, presumably due to the existence of many distinct subsets with different functions.2,3,8 Among these, CD4+ iNKT cells produce both TH 1 (such as interferon-g (IFN-g) and tumor necrosis factor a (TNF-a)) and TH 2 cytokines (such as interleukin-4 (IL-4), IL-10, and IL-13), and are associated with TH 0-type immune responses, whereas CD4– CD8– and CD4– CD8+ iNKT cells are similar and mainly produce TH 1 cytokines.1,2,11,12 Furthermore, a subset of iNKT cells that produces high amounts of cytokine IL-17 was recently
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NKT cells in pulmonary disorders
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Table 1 Classification of NKT and NKT-like cells Invariant NKT cells Type I NKT cells Classical NKT cells
Type II NKT cells Non-classical NKT cells
NKT-like cells
Antigen presentation
CD1d
CD1d
MHC
Antigen
Glycolipid
Hydrophobic & aromatic molecules
Peptide
TCR repertoire
Va24-Ja18 Vb11
Diverse
Diverse
NK cell markers
CD161+/– CD56+/–
CD161+/– CD56+/–
CD161 and/or CD56
Table 2 NKT and NKT-like cells in pulmonary disorders Disorder
Finding
Asthma
Altered numbers of iNKT cells (inconsistent results)
COPD
Increased numbers of iNKT and CD3+ CD56+ NKT-like cells in lungs, deficiency of CD3+ CD56+ NKT-like cells in peripheral blood
Sarcoidosis
Deficiency of iNKT cells
Hypersensitivity pneumonitis
Increased numbers of CD3+ CD16/CD56+ NKT-like cells, normal numbers of iNKT cells
Lung cancer
Deficiency and impaired function of iNKT cells
Tuberculosis
Deficiency of iNKT cells in active phase
identified.2,12–14 These iNKT cells are CD4– NK1.1– , which distinguishes them from the majority of other NKT cells and may have an important role in IL-17-mediated disease.2,13 The second group of CD1d-dependent cells, called also type II NKT cells, expresses an unbiased TCR repertoire and recognizes several hydrophobic antigens such as sulfatide, lysophosphatidylcholine, and aromatic molecules.2,15,16 These cells have been less thoroughly studied, mainly because they cannot be identified using a-GalCer-loaded CD1d tetramers. They are not discussed further in this review.
NKT-like cells The third group that resembles NKT cells, and is often referred to as NKT cells, are so-called NKT-like cells, or CD1d-independent T cells. These cells are independent of CD1d for their activity,3,6,10 and so they depend on the presentation of antigen to conventional MHC class I and II molecules and express unbiased a/b T-cell receptors. Other than the expression of CD161 and/or CD56, there is little evidence that these NKT-like cells are related to NKT cells.3,17 NKT-like cells comprise a highly heterogeneous group of cells, being either CD4+ , CD8+ , or double-negative CD4– CD8– T cells that also express NK-cell markers such as CD161 and/or CD56.3
Role of NKT cells in various disorders The roles of different subsets of NKT cells in humans are not completely understood, but it is well established that many have immunosuppressive activity and/or may promote enhanced cell-mediated immunity.18,19 NKT cells have been implicated in several biological processes, including cell-mediated suppression of tissue destruction,
anti-tumor responses, autoimmunity, host defense, allergy, and inflammation, as well as direct influences on B-cell proliferation and antibody production.1–3,20,21 Their role has mainly been associated with priming and regulating the immune response because numerical and/or functional impairments have been reported in many pulmonary disorders. Thus, NKT and NKT-like cells might play a critical role in several pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD), interstitial lung diseases such as sarcoidosis and hypersensitivity pneumonitis (HP), lung cancer, and infectious diseases such as tuberculosis (Table 2).1–3
Asthma Invariant NKT cells produce large amounts of both TH 1 and TH 2 cytokines and may either inhibit or exacerbate allergic response. Because asthma is characterized by a highly polarized TH 2 immune response, tissue inflammation, and airway hyperreactivity, various immune system cells, including NKT cells, have important roles in it. However, the reported results regarding the contribution of iNKT cells in asthma have been controversial. Early reports demonstrated an increased number of iNKT cells in the lungs of patients with asthma compared to patients with sarcoidosis and healthy controls.22–24 However, in subsequent years these findings were challenged by other groups, who reported lower iNKT cell counts than previously reported.25,26 Recent publications have highlighted the role of iNKT cells in asthma because several studies have shown a significant increase of iNKT cells in patients with asthma.27,28 Furthermore, it has been demonstrated that iNKT cells play an important role in the development of airway hyperreactivity and airway inflammation in mice and nonhuman primates,22,27 in which several environmental substances, including bacterial glycolipids, were shown to activate iNKT cells.29 It is
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now becoming evident that iNKT cells are involved in the pathogenesis of asthma because they might be employed as effectors as well as amplifiers of TH 2 cell response.30,31
Chronic obstructive pulmonary disease COPD is a disease consisting of emphysema, respiratory bronchiolitis and chronic bronchitis that is largely driven by TH 1-mediated immune responses.32,33 Increased levels of iNKT cells were found in the lung tissue of patients with COPD. Furthermore, interactions of CD4– iNKT cells with macrophages, subsequent activation and IL-13 production appears to be crucial for the development of chronic airway disease in animal mouse model.34 Beside that increased numbers as well as enhanced cytotoxicity of CD3+ CD56+ NKT-like cells in the induced sputum of COPD patients was observed, what is in contrary to what was observed in the peripheral blood. Therefore, those cells could be selectively recruited to the lungs.35,36 Furthermore, the proportion of CD8+ NKT-like cells was increased and CD4+ NKT-like cells were decreased in COPD patients. Therefore, CD8+ NKTlike cells with the production of predominantly TH 1-type cytokines could be responsible for the pro-inflammatory immune response in the lungs of COPD patients.36
Sarcoidosis Sarcoidosis is a multi-system disorder of unknown etiology that predominantly involves the lungs and is characterized by TH 1-biased CD4+ T cell response and the formation of granulomas. Other than evidence of T-cell involvement in the characteristic immune response, it is still unclear how this response is generated. The immunoregulatory properties of iNKT cells may play a very important role in sarcoidosis because loss of immunoregulation due to a deficiency and/or impaired function of these cells might contribute to the amplified and prolonged T-cell activity that characterizes sarcoidosis.37–40 Deficiencies of iNKT cells in the blood and bronchoalveolar lavage fluid (BALF) of sarcoidosis patients have been reported.37,38,40 The data on granulomas are inconsistent because there are reports on both the absence of iNKT cells in granulomatous38 and cutaneous lesions41 and also the accumulation of iNKT cells in granulomatous lesions of sarcoidosis patients.37 Furthermore, stimulated peripheral blood iNKT cells from sarcoidosis patients demonstrated impaired IFN-g production.37 A low number of iNKT cells and impaired IFN-g production might be involved in the inflammatory process in sarcoidosis and disease progression because the involvement of IFN-g in granuloma formation is well documented.37,39 However, longitudinal analysis of iNKT cell frequency and/or function throughout the course of the disease is needed to elucidate the exact role of these cells in the pathogenesis of sarcoidosis.
Hypersensitivity pneumonitis A recent study showed significantly higher CD3+ CD16/56+ NKT-like cell frequencies in the BALF of patients with HP compared to study cases with other interstitial lung diseases.42 Therefore, assessing the CD3+ CD16/56+ cells in the BALF might be a helpful adjunct in the diagnosis of
M. Rijavec et al.
HP. It was further demonstrated that a large proportion of the BALF cells of HP patients were of the CD8+ CD56+ subset, and the majority of these cells did not express the invariant Va24 T-cell receptor or CD161. Wajchman et al. showed that this distinct CD8+ CD56+ CD161– cell phenotype displays both antigen-specific (CTL-like) as well as NK-like cytolytic activities that are independent of HLA class I and CD1 molecules.10 Pittet et al. demonstrated that the potent cytolytic effector function of these cells closely correlates with CD56 surface expression and that these cells contain high amounts of intracellular perforin and granzyme B.43 The frequencies of iNKT cells in the BALF of HP patients were comparable to those in the BALF of healthy control subjects, and thus iNKT cells are unlikely to play an important role in the pathogenesis of HP.25,26,40 The increased number of CD8+ CD56+ cells in the BALF of HP patients is interesting from several points of view. First, animal models suggest that hypersensitivity pneumonitis is characterized by a TH 1-type response44 and that IFN-g is necessary for the development of disease because IFN-g knockout mice are resistant to developing hypersensitivity pneumonitis.45 Exposure to IL-12 further enhanced IFN-g production and consequently modulated the severity of experimental hypersensitivity pneumonitis.46 Yamasaki et al. demonstrated that clinical hypersensitivity pneumonitis is also characterized by a TH 1-type response and the predominance of IFN-g producing T cells.47 Therefore, the potential importance of NKT-like cells in hypersensitivity pneumonitis is strengthened by the findings that CD8+ CD56+ cells are more potent inducers of TH 1mediated immune response relative to CD8+ T cells and that the IL-12 stimulated CD8+ CD56+ cells can produce much larger amounts of IFN-g than CD8+ T cells.48 Second, the CD8+ CD56+ cells also have a unique chemokine receptor repertoire and a functional migratory response to the CCR5 ligand macrophage inflammatory protein-1 beta (MIP-1b).49 MIP-1b can markedly affect the mononuclear infiltration of the lung and was specifically detected in the BALF of HP patients compared to patients with sarcoidosis and cryptogenic fibrosing alveolitis.50
Lung cancer The pro-inflammatory activities of iNKT cells are important for the anti-tumor response in lung cancer. In particular, this includes the ability to induce secondary immune effects by producing INF-g and subsequently activating the conventional CD8+ T cells and NK cells.51,52 In addition, the perforin-dependent direct cytotoxicity of activated iNKT cells is also important.53 Compound action by NKT and NK cells is important for natural anti-tumor immunity.51–53 Decreased numbers and reduced functions of iNKT cells have been reported in peripheral blood of cancer patients as well as in tumor tissues.1,51,54 Furthermore, iNKT cells from cancer patients have been shown to have defective cytokine production because they produce less IFN-g than do iNKT cells from healthy individuals.54,55 Activation of iNKT cells also shows promising results in cancer immunotherapy. Administration of a-GalCer and the subsequent activation of iNKT, as well as treatment with in vitro-activated iNKT cells, have demonstrated clear clinical benefits in lung cancer. The therapy was well tolerated and induced an iNKT cellmodulated immune response, prolonging survival time in
NKT cells in pulmonary disorders non-small cell lung cancer patients.56–58 Seventeen patients with advanced non-small cell lung cancer refractory to the standard therapy, were treated with a-GalCer-pulsed autologous PBMCs. Ten patients who displayed increased IFN-g-producing cells showed significant prolongation of estimated median survival time (31.9 months; range, 14.5 to 36.3 months) as compared with poor-responder patients (9.7 months; range, 3.8 to 25.0 months).58
Infectious diseases: tuberculosis iNKT cells are able to exhibit both pro-inflammatory and anti-inflammatory properties; they have been implicated in bacterial, viral, fungal, protozoan, and helminthic infections. The immune response to microorganisms can be generated through iNKT cells’ recognition of glycolipid antigens present in pathogens or by indirect activation of iNKT cells in the presence of inflammatory cytokines against microorganisms that do not contain iNKT cell antigens.29,59 There is growing evidence that iNKT cell deficiency might be crucial for the development of active tuberculosis in patients infected with Mycobacterium tuberculosis because not only was iNKT cell deficiency associated with the active phase of the disease, but normal cell frequencies were also restored by treatment.1,60–62 However, further investigations are needed to determine the exact role of iNKT cells in tuberculosis, in addition to determining which subsets and antigens are responsible for activating iNKT cells and which specific cytokines are secreted during the course of disease.1,29
Therapeutic potential Immunotherapeutic interventions for the modulation of immune response by targeting immunoregulatory functions of iNKT cells has become a challenging field because it is established that these cells might play an important role in a wide range of disorders, including cancer, autoimmune diseases, and infections. Immunotherapeutic approaches targeting iNKT cells should restore proper immune system balance because various subsets and conditions of iNKT cells can either suppress or promote immune responses.1,4,21 Activation of iNKT cells by a-GalCer or its analogues has shown promising results in cancer therapy. Activated iNKT cells induced anti-tumor activities of other immune system subsets, such as B and CD8+ T cells. Therefore, administration of a-GalCer dendritic cells pulsed with a-GalCer or in vitro-activated iNKT cells are plausible novel cancer immunotherapies.56–58 Incorporation of glycolipids that activate iNKT cells, such as a-GalCer or its analogues, into the vaccine would allow us to tailor the immune response to it because it is known that iNKT cells can act as direct effector cells, and may modulate both adaptive and innate immunity.1,29 On the other hand, inhibition or blockade of iNKT with anti-CD1d antibodies, or especially a CD1d-dependent antagonist of iNKT cells such as dipalmitoyl-phosphatidyl ethanolamine (DPPE), protected against allergen-induced airway hyperreactivity in a mouse model, demonstrating possible clinical use in treating allergic asthma.63 The ability to specifically manipulate iNKT cells raises new possibilities for immunotherapeutic interventions in other diseases in which these cells play
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important roles, including infections and autoimmune diseases.
Conclusions NKT cells represent a bridge between innate and adaptive immunity. With their immunoregulatory functions, they have emerged as an important subset of lymphocytes with a protective role in some diseases, such as infections, cancer, and possibly sarcoidosis, and a pathogenic role in others, such as asthma. Modulation of the immunoregulatory functions of these cells has shown promising results for the development of new therapies.
Conflict of interest statement The authors declare that they have no competing interest.
References 1. Berzins SP, Smyth MJ, Baxter AG. Presumed guilty: natural killer T cell defects and human disease. Nat Rev Immunol 2011;11: 131–42. 2. Godfrey DI, Stankovic S, Baxter AG. Raising the NKT cell family. Nat Immunol 2010;11:197–206. 3. Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L. NKT cells: what’s in a name? Nat Rev Immunol 2004;4:231–7. 4. Van Kaer L, Vrajesh VP, Lan W. Invariant natural killer T cells: bridging innate and adaptive immunity. Cell Tissue Res 2011; 343:43–55. 5. Kronenberg M, Gapin L. The unconventional lifestyle of NKT cells. Nat Rev Immunol 2002;2:557–68. 6. Satoh M, Seki S, Hashimoto W, Ogasawara K, Kobayashi T, Kumagai K, et al. Cytotoxic gammadelta or alphabeta T cells with a natural killer cell marker, CD56, induced from human peripheral blood lymphocytes by a combination of IL-12 and IL-2. J Immunol 1996;157:3886–92. 7. Matsuda JL, Naidenko OV, Gapin L, Nakayama T, Taniguchi M, Wang CR, et al. Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers. J Exp Med 2000; 192:741–54. 8. Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol 2007;25:297–336. 9. Zhou D, Mattner J, Cantu C 3rd, Schrantz N, Yin N, Gao Y, et al. Lysosomal glycosphingolipid recognition by NKT cells. Science 2004;306:1786–9. 10. Wajchman HJ, Pierce CW, Varma VA, Issa MM, Petros J, Dombrowski KE. Ex vivo expansion of CD8+CD56+ and CD8+CD56– natural killer T cells specific for MUC1 mucin. Cancer Res 2004;64:1171–80. 11. Gumperz JE, Miyake S, Yamamura T, Brenner MB. Functionally distinct subsets of CD1d-restricted natural killer T cells revealed by CD1d tetramer staining. J Exp Med 2002;195:625–36. 12. Coquet JM, Chakravarti S, Kyparissoudis K, McNab FW, Pitt LA, McKenzie BS, et al. Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4–NK1.1–NKT cell population. Proc Natl Acad Sci U S A 2008;105:11287–92. 13. Michel ML, Keller AC, Paget C, Fujio M, Trottein F, Savage PB, et al. Identification of an IL-17-producing NK1.1(neg) iNKT cell population involved in airway neutrophilia. J Exp Med 2007; 204:995–1001. 14. Rachitskaya AV, Hansen AM, Horai R, Li Z, Villasmil R, Luger D, et al. Cutting edge: NKT cells constitutively express IL-23 receptor and RORgammat and rapidly produce IL-17 upon
S24
15.
16.
17.
18. 19.
20.
21. 22.
23.
24.
25.
26.
27.
28.
29.
30. 31.
32.
33. 34.
35.
M. Rijavec et al.
receptor ligation in an IL-6-independent fashion. J Immunol. 2008;180:5167–71. Jahng A, Maricic I, Aguilera C, Cardell S, Halder RC, Kumar V. Prevention of autoimmunity by targeting a distinct, noninvariant CD1d-reactive T cell population reactive to sulfatide. J Exp Med 2004;199:947–57. Van Rhijn I, Young DC, Im JS, Levery SB, Illarionov PA, Besra GS, et al. CD1d-restricted T cell activation by nonlipidic small molecules. Proc Natl Acad Sci U S A 2004;101:13578–83. Hammond KJ, Pelikan SB, Crowe NY, Randle-Barrett E, Nakayama T, Taniguchi M, et al. NKT cells are phenotypically and functionally diverse. Eur J Immunol 1999;29:3768–81. Smyth MJ, Godfrey DI. NKT cells and tumor immunity—a doubleedged sword. Nat Immunol 2000;1:459–60. Wilson SB, Delovitch TL. Janus-like role of regulatory iNKT cells in autoimmune disease and tumour immunity. Nat Rev Immunol 2003;3:211–22. Galli G, Nuti S, Tavarini S, Galli-Stampino L, De Lalla C, Casorati G, et al. Innate immune responses support adaptive immunity: NKT cells induce B cell activation. Vaccine 2003;21:S48–54. Seino K, Taniguchi M. Functionally distinct NKT cell subsets and subtypes. J Exp Med 2005;202:1623–6. Akbari O, Faul JL, Hoyte EG, Berry GJ, Wahlstrom J, Kronenberg M, et al. CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma. N Engl J Med 2006;354: 1117–29. Pham-Thi N, deBlic J, LeBourgeois M, Dy M, Scheinmann P, Leite-de-Moraes MC. Enhanced frequency of immunoregulatory invariant natural killer T cells in the airways of children with asthma. J Allergy Clin Immunol 2006;117:217–8. Hamzaoui 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. Vijayanand P, Seumois G, Pickard C, Powell RM, Angco G, Sammut D, et al. Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease. N Engl J Med 2007;356:1410–22. Mutalithas 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;119:1274–6. Matangkasombut P, Pichavant M, Yasumi T, Hendricks C, Savage PB, Dekruyff RH, et al. Direct activation of natural killer T cells induces airway hyperreactivity in nonhuman primates. J Allergy Clin Immunol 2008;121:1287–9. Koh YI, Shim JU. Association between sputum natural killer T cells and eosinophilic airway inflammation in human asthma. Int Arch Allergy Immunol 2010;153:239–48. Tupin E, Kinjo Y, Kronenberg M. The unique role of natural killer T cells in the response to microorganisms. Nat Rev Microbiol 2007;5:405–17. Iwamura C, Nakayama T. Role of NKT cells in allergic asthma. Curr Opin Immunol 2010;22:807–13. Umetsu DT, Dekruyff RH. Natural killer T cells are important in the pathogenesis of asthma: the many pathways to asthma. J Allergy Clin Immunol 2010;125:975–9. Molfino NA, Jeffery PK. Chronic obstructive pulmonary disease: histopathology, inflammation and potential therapies. Pulm Pharmacol Ther 2007;20:462–72. Joyce S, Van Kaer L. Lung NKT cell commotion takes your breath away. Nat Med 2008;14:609–10. Kim EY, Battaile JT, Patel AC, You Y, Agapov E, Grayson MH, et al. Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat Med 2008;14:633–40. Urbanowicz RA, Lamb JR, Todd I, Corne JM, Fairclough LC.
36.
37.
38.
39. 40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52. 53.
54.
Altered effector function of peripheral cytotoxic cells in COPD. Respir Res 2009;10:53. Urbanowicz RA, Lamb JR, Todd I, Corne JM, Fairclough LC. Enhanced effector function of cytotoxic cells in the induced sputum of COPD patients. Respir Res 2010;11:76. Kobayashi S, Kaneko Y, Seino K, Yamada Y, Motohashi S, Koike J, et al. Impaired IFN-gamma production of Valpha24 NKT cells in non-remitting sarcoidosis. Int Immunol 2004;16:215–22. Ho LP, Urban BC, Thickett DR, Davies RJ, McMichael AJ. Deficiency of a subset of T-cells with immunoregulatory properties in sarcoidosis. Lancet 2005;365:1062–72. Grunewald J, Eklund A. Role of CD4+ T cells in sarcoidosis. Proc Am Thorac Soc 2007;15:461–4. Koroˇsec P, Rijavec M, Silar M, Kern I, Koˇsnik M, Osolnik K. Deficiency of pulmonary Valpha24 Vbeta11 natural killer T cells in corticosteroid-naïve sarcoidosis patients. Respir Med 2010;104:571–7. Mempel M, Flageul B, Suarez F, Ronet C, Dubertret L, Kourilsky P, et al. Comparison of the T cell patterns in leprous and cutaneous sarcoid granulomas. Presence of Valpha24-invariant natural killer T cells in T-cell-reactive leprosy together with a highly biased T cell receptor Valpha repertoire. Am J Pathol 2000;157:509–23. Koroˇsec P, Osolnik K, Kern I, Silar M, Mohorˇ ciˇ c K, Koˇsnik M. Expansion of pulmonary CD8+CD56+ natural killer T-cells in hypersensitivity pneumonitis. Chest 2007;132:1291–7. Pittet MJ, Speiser DE, Valmori D, Cerottini JC, Romero P. Cutting edge: cytolytic effector function in human circulating CD8+ T cells closely correlates with CD56 surface expression. J Immunol 2000;164:1148–52. Schuyler M, Gott K, Cherne A, Edwards B. Th1 CD4+ cells adoptively transfer experimental hypersensitivity pneumonitis. Cell Immunol 1997;177:169–75. Gudmundsson G, Hunninghake GW. Interferon-gamma is necessary for the expression of hypersensitivity pneumonitis. J Clin Invest 1997;99:2386–90. Gudmundsson G, Monick MM, Hunninghake GW. IL-12 modulates expression of hypersensitivity pneumonitis. J Immunol 1998; 161:991–9. Yamasaki H, Ando M, Brazer W, Center DM, Cruikshank WW. Polarized type 1 cytokine profile in bronchoalveolar lavage T cells of patients with hypersensitivity pneumonitis. J Immunol 1999;163:3516–23. Ohkawa T, Seki S, Dobashi H, Koike Y, Habu Y, Ami K, et al. Systematic characterization of human CD8+ T cells with natural killer cell markers in comparison with natural killer cells and normal CD8+ T cells. Immunology 2001;103:281–90. Campbell JJ, Qin S, Unutmaz D, Soler D, Murphy KE, Hodge MR, et al. Unique subpopulations of CD56+ NK and NK-T peripheral blood lymphocytes identified by chemokine receptor expression repertoire. J Immunol 2001;166:6477–82. Oshima M, Maeda A, Ishioka S, Hiyama K, Yamakido M. Expression of C-C chemokines in bronchoalveolar lavage cells from patients with granulomatous lung diseases. Lung 1999;177:229–40. Konishi J, Yamazaki K, Yokouchi H, Shinagawa N, Iwabuchi K, Nishimura M. The characteristics of human NKT cells in lung cancer-CD1d independent cytotoxicity against lung cancer cells by NKT cells and decreased human NKT cell response in lung cancer patients. Hum Immunol 2004;65:1377–88. Terabe M, Berzofsky JA. The role of NKT cells in tumor immunity. Adv Cancer Res 2008;101:277–348. Seino K, Motohashi S, Fujisawa T, Nakayama T, Taniguchi M. Natural killer T cell-mediated antitumor immune responses and their clinical applications. Cancer Sci 2006;97:807–12. Molling JW, K¨ olgen W, van der Vliet HJ, Boomsma MF, Kruizenga H, Smorenburg CH, et al. Peripheral blood IFN-gsecreting Va24+Vb11+ NKT cell numbers are decreased in cancer
NKT cells in pulmonary disorders
55.
56.
57.
58.
patients independent of tumor type or tumor load. Int J Cancer 2005;116:87–93. Tahir SM, Cheng O, Shaulov A, Koezuka Y, Bubley GJ, Wilson SB, et al. Loss of IFN-g production by invariant NK T cells in advanced cancer. J Immunol 2001;167:4046–50. Motohashi S, Okamoto Y, Yoshino I, Nakayama T. Anti-tumor immune responses induced by iNKT cell-based immunotherapy for lung cancer and head and neck cancer. Clinical Immunology 2009 doi:10.1016/j.clim.2011.01.009. Taniguchi M, Tashiro T, Dashtsoodol N, Hongo N, Watarai H. The specialized iNKT cell system recognizes glycolipid antigens and bridges the innate and acquired immune systems with potential applications for cancer therapy. Int Immunol 2010;22:1–6. Motohashi S, Nagato K, Kunii N, Yamamoto H, Yamasaki K, Okita K, et al. A phase I-II study of alpha-galactosylceramidepulsed IL-2/GM-CSF-cultured peripheral blood mononuclear cells in patients with advanced and recurrent non-small cell lung cancer. J Immunol 2009;182:2492–501.
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59. Godfrey DI, Kronenberg M. Going both ways: immune regulation via CD1d-dependent NKT cells. J Clin Invest 2004;114:1379–88. 60. Sutherland JS, Jeffries DJ, Donkor S, Walther B, Hill PC, Adetifa IM, et al. High granulocyte/lymphocyte ratio and paucity of NKT cells defines TB disease in a TB-endemic setting. Tuberculosis 2009;89:398–404. 61. Montoya CJ, Cata˜ no JC, Ramirez Z, Rugeles MT, Wilson SB, Landay AL. Invariant NKT cells from HIV-1 or Mycobacterium tuberculosis-infected patients express an activated phenotype. Clin Immunol 2008;127:1–6. 62. Im JS, Kang TJ, Lee SB, Kim CH, Lee SH, Venkataswamy MM, et al. Alteration of the relative levels of iNKT cell subsets is associated with chronic mycobacterial infections. Clin Immunol 2008;127:214–24. 63. Lombardi V, Stock P, Singh AK, Kerzerho J, Yang W, Sullivan BA, et al. A CD1d-dependent antagonist inhibits the activation of invariant NKT cells and prevents development of allergeninduced airway hyperreactivity. J Immunol 2010;184:2107–15.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/rmed
Natural killer T cells in pulmonary disorders Matija Rijaveca , Sinisa Volarevicb , Katarina Osolnika , Mitja Kosnika , Peter Koroseca a b
University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia Department of Molecular Medicine and Biotechnology, School of Medicine, University of Rijeka, Croatia
KEYWORDS Asthma; COPD; Hypersensitivity; Lung cancer; NKT cells; Pneumonitis; Sarcoidosis; Tuberculosis
Summary Natural killer T (NKT) cells, a unique subgroup of lymphocytes with features of both T and natural killer (NK) cells, represent a bridge between innate and adaptive immunity. They have the ability to either promote or suppress immune responses. With these immunoregulatory functions, NKT cells have emerged as an important subset of lymphocytes with a protective role in some disorders, such as infections, cancer, and possibly sarcoidosis, and a pathogenic role in others, such as asthma, chronic obstructive pulmonary disease and hypersensitivity pneumonitis. Immunotherapeutic interventions to modulate the immune response by targeting iNKT cell functions has become a challenging field and has shown promising results for the development of new therapies. © 2011 Elsevier Ltd. All rights reserved.
NKT cell heterogeneity Natural killer T (NKT) cells and NKT-like cells comprise a unique, yet highly heterogeneous subgroup of lymphocytes that express features of both T cells and natural killer (NK) cells and coexpress T-cell receptors (TCRs) together with markers associated with NK cells, such as CD56 and/or CD161.1–3 These cells are phenotypically and functionally highly diverse, but all are hybrid by nature and represent a bridge between innate and adaptive immunity (Table 1). Along with macrophages, dendritic cells, and others, NK cells are part of the innate immune system, whereas the acquired immune system is defined by the clonal expansion of antigen-specific T and B cells and their memory immune responses. Because NKT and NKT-like cells are part of both systems, their absence, depletion, or improper function affects both innate and acquired immunity.1–4
Type I and Type II NKT cells In humans there are two major subsets of NKT cells that are dependent on the presentation of the antigen through CD1d, a nonpolymorphic class I antigen-presenting molecule. CD1d is expressed on many different cells, including dendritic * Corresponding author. Matija Rijavec. University Clinic of Respiratory and Allergic Diseases, Golnik 36, 4204 Golnik, Slovenia. E-mail: [email protected] (M. Rijavec).
cells, thymocytes, B cells, monocytes, and macrophages. When glycolipid antigen binds to CD1d, the antigen/CD1d complex binds to the TCR of NKT cells.2,5 The most widely studied are CD1d-dependent cells, which express a highly restricted TCR with an invariant Va24-Ja18 preferentially paired with Vb11. These are called invariant NKT (iNKT) cells or type I NKT cells.1,2,4,6 The best-known iNKT cell antigen is the glycolipid a-galactosylceramide (a-GalCer), originally isolated from the marine sponge Agelas mauritianus, which is also used to identify cells as a-GalCer-loaded CD1d tetramers.1,7 Other glycolipid antigens for iNKT cells have been identified, including bacterial glycolipids such as a-galacturonosylceramide, a-glucuronosylceramide, and a-galactosyl-diacylglycerol, as well as mammalian glycolipids such as isoglobotrihexosylceramide (iGb3) and the disialoganglioside GD3.2,8,9 Activated iNKT cells rapidly release large amounts of both T-helper 1 (TH 1), TH 2, and/or TH 17-specific cytokines and exhibit both antigen-specific and NK-like cytolytic activities.1,2,5,10 Invariant NKT cells are therefore able to both promote and suppress immune responses, presumably due to the existence of many distinct subsets with different functions.2,3,8 Among these, CD4+ iNKT cells produce both TH 1 (such as interferon-g (IFN-g) and tumor necrosis factor a (TNF-a)) and TH 2 cytokines (such as interleukin-4 (IL-4), IL-10, and IL-13), and are associated with TH 0-type immune responses, whereas CD4– CD8– and CD4– CD8+ iNKT cells are similar and mainly produce TH 1 cytokines.1,2,11,12 Furthermore, a subset of iNKT cells that produces high amounts of cytokine IL-17 was recently
0954-6111$ – see front matter © 2011 Elsevier Ltd. All rights reserved.
NKT cells in pulmonary disorders
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Table 1 Classification of NKT and NKT-like cells Invariant NKT cells Type I NKT cells Classical NKT cells
Type II NKT cells Non-classical NKT cells
NKT-like cells
Antigen presentation
CD1d
CD1d
MHC
Antigen
Glycolipid
Hydrophobic & aromatic molecules
Peptide
TCR repertoire
Va24-Ja18 Vb11
Diverse
Diverse
NK cell markers
CD161+/– CD56+/–
CD161+/– CD56+/–
CD161 and/or CD56
Table 2 NKT and NKT-like cells in pulmonary disorders Disorder
Finding
Asthma
Altered numbers of iNKT cells (inconsistent results)
COPD
Increased numbers of iNKT and CD3+ CD56+ NKT-like cells in lungs, deficiency of CD3+ CD56+ NKT-like cells in peripheral blood
Sarcoidosis
Deficiency of iNKT cells
Hypersensitivity pneumonitis
Increased numbers of CD3+ CD16/CD56+ NKT-like cells, normal numbers of iNKT cells
Lung cancer
Deficiency and impaired function of iNKT cells
Tuberculosis
Deficiency of iNKT cells in active phase
identified.2,12–14 These iNKT cells are CD4– NK1.1– , which distinguishes them from the majority of other NKT cells and may have an important role in IL-17-mediated disease.2,13 The second group of CD1d-dependent cells, called also type II NKT cells, expresses an unbiased TCR repertoire and recognizes several hydrophobic antigens such as sulfatide, lysophosphatidylcholine, and aromatic molecules.2,15,16 These cells have been less thoroughly studied, mainly because they cannot be identified using a-GalCer-loaded CD1d tetramers. They are not discussed further in this review.
NKT-like cells The third group that resembles NKT cells, and is often referred to as NKT cells, are so-called NKT-like cells, or CD1d-independent T cells. These cells are independent of CD1d for their activity,3,6,10 and so they depend on the presentation of antigen to conventional MHC class I and II molecules and express unbiased a/b T-cell receptors. Other than the expression of CD161 and/or CD56, there is little evidence that these NKT-like cells are related to NKT cells.3,17 NKT-like cells comprise a highly heterogeneous group of cells, being either CD4+ , CD8+ , or double-negative CD4– CD8– T cells that also express NK-cell markers such as CD161 and/or CD56.3
Role of NKT cells in various disorders The roles of different subsets of NKT cells in humans are not completely understood, but it is well established that many have immunosuppressive activity and/or may promote enhanced cell-mediated immunity.18,19 NKT cells have been implicated in several biological processes, including cell-mediated suppression of tissue destruction,
anti-tumor responses, autoimmunity, host defense, allergy, and inflammation, as well as direct influences on B-cell proliferation and antibody production.1–3,20,21 Their role has mainly been associated with priming and regulating the immune response because numerical and/or functional impairments have been reported in many pulmonary disorders. Thus, NKT and NKT-like cells might play a critical role in several pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD), interstitial lung diseases such as sarcoidosis and hypersensitivity pneumonitis (HP), lung cancer, and infectious diseases such as tuberculosis (Table 2).1–3
Asthma Invariant NKT cells produce large amounts of both TH 1 and TH 2 cytokines and may either inhibit or exacerbate allergic response. Because asthma is characterized by a highly polarized TH 2 immune response, tissue inflammation, and airway hyperreactivity, various immune system cells, including NKT cells, have important roles in it. However, the reported results regarding the contribution of iNKT cells in asthma have been controversial. Early reports demonstrated an increased number of iNKT cells in the lungs of patients with asthma compared to patients with sarcoidosis and healthy controls.22–24 However, in subsequent years these findings were challenged by other groups, who reported lower iNKT cell counts than previously reported.25,26 Recent publications have highlighted the role of iNKT cells in asthma because several studies have shown a significant increase of iNKT cells in patients with asthma.27,28 Furthermore, it has been demonstrated that iNKT cells play an important role in the development of airway hyperreactivity and airway inflammation in mice and nonhuman primates,22,27 in which several environmental substances, including bacterial glycolipids, were shown to activate iNKT cells.29 It is
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now becoming evident that iNKT cells are involved in the pathogenesis of asthma because they might be employed as effectors as well as amplifiers of TH 2 cell response.30,31
Chronic obstructive pulmonary disease COPD is a disease consisting of emphysema, respiratory bronchiolitis and chronic bronchitis that is largely driven by TH 1-mediated immune responses.32,33 Increased levels of iNKT cells were found in the lung tissue of patients with COPD. Furthermore, interactions of CD4– iNKT cells with macrophages, subsequent activation and IL-13 production appears to be crucial for the development of chronic airway disease in animal mouse model.34 Beside that increased numbers as well as enhanced cytotoxicity of CD3+ CD56+ NKT-like cells in the induced sputum of COPD patients was observed, what is in contrary to what was observed in the peripheral blood. Therefore, those cells could be selectively recruited to the lungs.35,36 Furthermore, the proportion of CD8+ NKT-like cells was increased and CD4+ NKT-like cells were decreased in COPD patients. Therefore, CD8+ NKTlike cells with the production of predominantly TH 1-type cytokines could be responsible for the pro-inflammatory immune response in the lungs of COPD patients.36
Sarcoidosis Sarcoidosis is a multi-system disorder of unknown etiology that predominantly involves the lungs and is characterized by TH 1-biased CD4+ T cell response and the formation of granulomas. Other than evidence of T-cell involvement in the characteristic immune response, it is still unclear how this response is generated. The immunoregulatory properties of iNKT cells may play a very important role in sarcoidosis because loss of immunoregulation due to a deficiency and/or impaired function of these cells might contribute to the amplified and prolonged T-cell activity that characterizes sarcoidosis.37–40 Deficiencies of iNKT cells in the blood and bronchoalveolar lavage fluid (BALF) of sarcoidosis patients have been reported.37,38,40 The data on granulomas are inconsistent because there are reports on both the absence of iNKT cells in granulomatous38 and cutaneous lesions41 and also the accumulation of iNKT cells in granulomatous lesions of sarcoidosis patients.37 Furthermore, stimulated peripheral blood iNKT cells from sarcoidosis patients demonstrated impaired IFN-g production.37 A low number of iNKT cells and impaired IFN-g production might be involved in the inflammatory process in sarcoidosis and disease progression because the involvement of IFN-g in granuloma formation is well documented.37,39 However, longitudinal analysis of iNKT cell frequency and/or function throughout the course of the disease is needed to elucidate the exact role of these cells in the pathogenesis of sarcoidosis.
Hypersensitivity pneumonitis A recent study showed significantly higher CD3+ CD16/56+ NKT-like cell frequencies in the BALF of patients with HP compared to study cases with other interstitial lung diseases.42 Therefore, assessing the CD3+ CD16/56+ cells in the BALF might be a helpful adjunct in the diagnosis of
M. Rijavec et al.
HP. It was further demonstrated that a large proportion of the BALF cells of HP patients were of the CD8+ CD56+ subset, and the majority of these cells did not express the invariant Va24 T-cell receptor or CD161. Wajchman et al. showed that this distinct CD8+ CD56+ CD161– cell phenotype displays both antigen-specific (CTL-like) as well as NK-like cytolytic activities that are independent of HLA class I and CD1 molecules.10 Pittet et al. demonstrated that the potent cytolytic effector function of these cells closely correlates with CD56 surface expression and that these cells contain high amounts of intracellular perforin and granzyme B.43 The frequencies of iNKT cells in the BALF of HP patients were comparable to those in the BALF of healthy control subjects, and thus iNKT cells are unlikely to play an important role in the pathogenesis of HP.25,26,40 The increased number of CD8+ CD56+ cells in the BALF of HP patients is interesting from several points of view. First, animal models suggest that hypersensitivity pneumonitis is characterized by a TH 1-type response44 and that IFN-g is necessary for the development of disease because IFN-g knockout mice are resistant to developing hypersensitivity pneumonitis.45 Exposure to IL-12 further enhanced IFN-g production and consequently modulated the severity of experimental hypersensitivity pneumonitis.46 Yamasaki et al. demonstrated that clinical hypersensitivity pneumonitis is also characterized by a TH 1-type response and the predominance of IFN-g producing T cells.47 Therefore, the potential importance of NKT-like cells in hypersensitivity pneumonitis is strengthened by the findings that CD8+ CD56+ cells are more potent inducers of TH 1mediated immune response relative to CD8+ T cells and that the IL-12 stimulated CD8+ CD56+ cells can produce much larger amounts of IFN-g than CD8+ T cells.48 Second, the CD8+ CD56+ cells also have a unique chemokine receptor repertoire and a functional migratory response to the CCR5 ligand macrophage inflammatory protein-1 beta (MIP-1b).49 MIP-1b can markedly affect the mononuclear infiltration of the lung and was specifically detected in the BALF of HP patients compared to patients with sarcoidosis and cryptogenic fibrosing alveolitis.50
Lung cancer The pro-inflammatory activities of iNKT cells are important for the anti-tumor response in lung cancer. In particular, this includes the ability to induce secondary immune effects by producing INF-g and subsequently activating the conventional CD8+ T cells and NK cells.51,52 In addition, the perforin-dependent direct cytotoxicity of activated iNKT cells is also important.53 Compound action by NKT and NK cells is important for natural anti-tumor immunity.51–53 Decreased numbers and reduced functions of iNKT cells have been reported in peripheral blood of cancer patients as well as in tumor tissues.1,51,54 Furthermore, iNKT cells from cancer patients have been shown to have defective cytokine production because they produce less IFN-g than do iNKT cells from healthy individuals.54,55 Activation of iNKT cells also shows promising results in cancer immunotherapy. Administration of a-GalCer and the subsequent activation of iNKT, as well as treatment with in vitro-activated iNKT cells, have demonstrated clear clinical benefits in lung cancer. The therapy was well tolerated and induced an iNKT cellmodulated immune response, prolonging survival time in
NKT cells in pulmonary disorders non-small cell lung cancer patients.56–58 Seventeen patients with advanced non-small cell lung cancer refractory to the standard therapy, were treated with a-GalCer-pulsed autologous PBMCs. Ten patients who displayed increased IFN-g-producing cells showed significant prolongation of estimated median survival time (31.9 months; range, 14.5 to 36.3 months) as compared with poor-responder patients (9.7 months; range, 3.8 to 25.0 months).58
Infectious diseases: tuberculosis iNKT cells are able to exhibit both pro-inflammatory and anti-inflammatory properties; they have been implicated in bacterial, viral, fungal, protozoan, and helminthic infections. The immune response to microorganisms can be generated through iNKT cells’ recognition of glycolipid antigens present in pathogens or by indirect activation of iNKT cells in the presence of inflammatory cytokines against microorganisms that do not contain iNKT cell antigens.29,59 There is growing evidence that iNKT cell deficiency might be crucial for the development of active tuberculosis in patients infected with Mycobacterium tuberculosis because not only was iNKT cell deficiency associated with the active phase of the disease, but normal cell frequencies were also restored by treatment.1,60–62 However, further investigations are needed to determine the exact role of iNKT cells in tuberculosis, in addition to determining which subsets and antigens are responsible for activating iNKT cells and which specific cytokines are secreted during the course of disease.1,29
Therapeutic potential Immunotherapeutic interventions for the modulation of immune response by targeting immunoregulatory functions of iNKT cells has become a challenging field because it is established that these cells might play an important role in a wide range of disorders, including cancer, autoimmune diseases, and infections. Immunotherapeutic approaches targeting iNKT cells should restore proper immune system balance because various subsets and conditions of iNKT cells can either suppress or promote immune responses.1,4,21 Activation of iNKT cells by a-GalCer or its analogues has shown promising results in cancer therapy. Activated iNKT cells induced anti-tumor activities of other immune system subsets, such as B and CD8+ T cells. Therefore, administration of a-GalCer dendritic cells pulsed with a-GalCer or in vitro-activated iNKT cells are plausible novel cancer immunotherapies.56–58 Incorporation of glycolipids that activate iNKT cells, such as a-GalCer or its analogues, into the vaccine would allow us to tailor the immune response to it because it is known that iNKT cells can act as direct effector cells, and may modulate both adaptive and innate immunity.1,29 On the other hand, inhibition or blockade of iNKT with anti-CD1d antibodies, or especially a CD1d-dependent antagonist of iNKT cells such as dipalmitoyl-phosphatidyl ethanolamine (DPPE), protected against allergen-induced airway hyperreactivity in a mouse model, demonstrating possible clinical use in treating allergic asthma.63 The ability to specifically manipulate iNKT cells raises new possibilities for immunotherapeutic interventions in other diseases in which these cells play
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important roles, including infections and autoimmune diseases.
Conclusions NKT cells represent a bridge between innate and adaptive immunity. With their immunoregulatory functions, they have emerged as an important subset of lymphocytes with a protective role in some diseases, such as infections, cancer, and possibly sarcoidosis, and a pathogenic role in others, such as asthma. Modulation of the immunoregulatory functions of these cells has shown promising results for the development of new therapies.
Conflict of interest statement The authors declare that they have no competing interest.
References 1. Berzins SP, Smyth MJ, Baxter AG. Presumed guilty: natural killer T cell defects and human disease. Nat Rev Immunol 2011;11: 131–42. 2. Godfrey DI, Stankovic S, Baxter AG. Raising the NKT cell family. Nat Immunol 2010;11:197–206. 3. Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L. NKT cells: what’s in a name? Nat Rev Immunol 2004;4:231–7. 4. Van Kaer L, Vrajesh VP, Lan W. Invariant natural killer T cells: bridging innate and adaptive immunity. Cell Tissue Res 2011; 343:43–55. 5. Kronenberg M, Gapin L. The unconventional lifestyle of NKT cells. Nat Rev Immunol 2002;2:557–68. 6. Satoh M, Seki S, Hashimoto W, Ogasawara K, Kobayashi T, Kumagai K, et al. Cytotoxic gammadelta or alphabeta T cells with a natural killer cell marker, CD56, induced from human peripheral blood lymphocytes by a combination of IL-12 and IL-2. J Immunol 1996;157:3886–92. 7. Matsuda JL, Naidenko OV, Gapin L, Nakayama T, Taniguchi M, Wang CR, et al. Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers. J Exp Med 2000; 192:741–54. 8. Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol 2007;25:297–336. 9. Zhou D, Mattner J, Cantu C 3rd, Schrantz N, Yin N, Gao Y, et al. Lysosomal glycosphingolipid recognition by NKT cells. Science 2004;306:1786–9. 10. Wajchman HJ, Pierce CW, Varma VA, Issa MM, Petros J, Dombrowski KE. Ex vivo expansion of CD8+CD56+ and CD8+CD56– natural killer T cells specific for MUC1 mucin. Cancer Res 2004;64:1171–80. 11. Gumperz JE, Miyake S, Yamamura T, Brenner MB. Functionally distinct subsets of CD1d-restricted natural killer T cells revealed by CD1d tetramer staining. J Exp Med 2002;195:625–36. 12. Coquet JM, Chakravarti S, Kyparissoudis K, McNab FW, Pitt LA, McKenzie BS, et al. Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4–NK1.1–NKT cell population. Proc Natl Acad Sci U S A 2008;105:11287–92. 13. Michel ML, Keller AC, Paget C, Fujio M, Trottein F, Savage PB, et al. Identification of an IL-17-producing NK1.1(neg) iNKT cell population involved in airway neutrophilia. J Exp Med 2007; 204:995–1001. 14. Rachitskaya AV, Hansen AM, Horai R, Li Z, Villasmil R, Luger D, et al. Cutting edge: NKT cells constitutively express IL-23 receptor and RORgammat and rapidly produce IL-17 upon
S24
15.
16.
17.
18. 19.
20.
21. 22.
23.
24.
25.
26.
27.
28.
29.
30. 31.
32.
33. 34.
35.
M. Rijavec et al.
receptor ligation in an IL-6-independent fashion. J Immunol. 2008;180:5167–71. Jahng A, Maricic I, Aguilera C, Cardell S, Halder RC, Kumar V. Prevention of autoimmunity by targeting a distinct, noninvariant CD1d-reactive T cell population reactive to sulfatide. J Exp Med 2004;199:947–57. Van Rhijn I, Young DC, Im JS, Levery SB, Illarionov PA, Besra GS, et al. CD1d-restricted T cell activation by nonlipidic small molecules. Proc Natl Acad Sci U S A 2004;101:13578–83. Hammond KJ, Pelikan SB, Crowe NY, Randle-Barrett E, Nakayama T, Taniguchi M, et al. NKT cells are phenotypically and functionally diverse. Eur J Immunol 1999;29:3768–81. Smyth MJ, Godfrey DI. NKT cells and tumor immunity—a doubleedged sword. Nat Immunol 2000;1:459–60. Wilson SB, Delovitch TL. Janus-like role of regulatory iNKT cells in autoimmune disease and tumour immunity. Nat Rev Immunol 2003;3:211–22. Galli G, Nuti S, Tavarini S, Galli-Stampino L, De Lalla C, Casorati G, et al. Innate immune responses support adaptive immunity: NKT cells induce B cell activation. Vaccine 2003;21:S48–54. Seino K, Taniguchi M. Functionally distinct NKT cell subsets and subtypes. J Exp Med 2005;202:1623–6. Akbari O, Faul JL, Hoyte EG, Berry GJ, Wahlstrom J, Kronenberg M, et al. CD4+ invariant T-cell-receptor+ natural killer T cells in bronchial asthma. N Engl J Med 2006;354: 1117–29. Pham-Thi N, deBlic J, LeBourgeois M, Dy M, Scheinmann P, Leite-de-Moraes MC. Enhanced frequency of immunoregulatory invariant natural killer T cells in the airways of children with asthma. J Allergy Clin Immunol 2006;117:217–8. Hamzaoui 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. Vijayanand P, Seumois G, Pickard C, Powell RM, Angco G, Sammut D, et al. Invariant natural killer T cells in asthma and chronic obstructive pulmonary disease. N Engl J Med 2007;356:1410–22. Mutalithas 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;119:1274–6. Matangkasombut P, Pichavant M, Yasumi T, Hendricks C, Savage PB, Dekruyff RH, et al. Direct activation of natural killer T cells induces airway hyperreactivity in nonhuman primates. J Allergy Clin Immunol 2008;121:1287–9. Koh YI, Shim JU. Association between sputum natural killer T cells and eosinophilic airway inflammation in human asthma. Int Arch Allergy Immunol 2010;153:239–48. Tupin E, Kinjo Y, Kronenberg M. The unique role of natural killer T cells in the response to microorganisms. Nat Rev Microbiol 2007;5:405–17. Iwamura C, Nakayama T. Role of NKT cells in allergic asthma. Curr Opin Immunol 2010;22:807–13. Umetsu DT, Dekruyff RH. Natural killer T cells are important in the pathogenesis of asthma: the many pathways to asthma. J Allergy Clin Immunol 2010;125:975–9. Molfino NA, Jeffery PK. Chronic obstructive pulmonary disease: histopathology, inflammation and potential therapies. Pulm Pharmacol Ther 2007;20:462–72. Joyce S, Van Kaer L. Lung NKT cell commotion takes your breath away. Nat Med 2008;14:609–10. Kim EY, Battaile JT, Patel AC, You Y, Agapov E, Grayson MH, et al. Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat Med 2008;14:633–40. Urbanowicz RA, Lamb JR, Todd I, Corne JM, Fairclough LC.
36.
37.
38.
39. 40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52. 53.
54.
Altered effector function of peripheral cytotoxic cells in COPD. Respir Res 2009;10:53. Urbanowicz RA, Lamb JR, Todd I, Corne JM, Fairclough LC. Enhanced effector function of cytotoxic cells in the induced sputum of COPD patients. Respir Res 2010;11:76. Kobayashi S, Kaneko Y, Seino K, Yamada Y, Motohashi S, Koike J, et al. Impaired IFN-gamma production of Valpha24 NKT cells in non-remitting sarcoidosis. Int Immunol 2004;16:215–22. Ho LP, Urban BC, Thickett DR, Davies RJ, McMichael AJ. Deficiency of a subset of T-cells with immunoregulatory properties in sarcoidosis. Lancet 2005;365:1062–72. Grunewald J, Eklund A. Role of CD4+ T cells in sarcoidosis. Proc Am Thorac Soc 2007;15:461–4. Koroˇsec P, Rijavec M, Silar M, Kern I, Koˇsnik M, Osolnik K. Deficiency of pulmonary Valpha24 Vbeta11 natural killer T cells in corticosteroid-naïve sarcoidosis patients. Respir Med 2010;104:571–7. Mempel M, Flageul B, Suarez F, Ronet C, Dubertret L, Kourilsky P, et al. Comparison of the T cell patterns in leprous and cutaneous sarcoid granulomas. Presence of Valpha24-invariant natural killer T cells in T-cell-reactive leprosy together with a highly biased T cell receptor Valpha repertoire. Am J Pathol 2000;157:509–23. Koroˇsec P, Osolnik K, Kern I, Silar M, Mohorˇ ciˇ c K, Koˇsnik M. Expansion of pulmonary CD8+CD56+ natural killer T-cells in hypersensitivity pneumonitis. Chest 2007;132:1291–7. Pittet MJ, Speiser DE, Valmori D, Cerottini JC, Romero P. Cutting edge: cytolytic effector function in human circulating CD8+ T cells closely correlates with CD56 surface expression. J Immunol 2000;164:1148–52. Schuyler M, Gott K, Cherne A, Edwards B. Th1 CD4+ cells adoptively transfer experimental hypersensitivity pneumonitis. Cell Immunol 1997;177:169–75. Gudmundsson G, Hunninghake GW. Interferon-gamma is necessary for the expression of hypersensitivity pneumonitis. J Clin Invest 1997;99:2386–90. Gudmundsson G, Monick MM, Hunninghake GW. IL-12 modulates expression of hypersensitivity pneumonitis. J Immunol 1998; 161:991–9. Yamasaki H, Ando M, Brazer W, Center DM, Cruikshank WW. Polarized type 1 cytokine profile in bronchoalveolar lavage T cells of patients with hypersensitivity pneumonitis. J Immunol 1999;163:3516–23. Ohkawa T, Seki S, Dobashi H, Koike Y, Habu Y, Ami K, et al. Systematic characterization of human CD8+ T cells with natural killer cell markers in comparison with natural killer cells and normal CD8+ T cells. Immunology 2001;103:281–90. Campbell JJ, Qin S, Unutmaz D, Soler D, Murphy KE, Hodge MR, et al. Unique subpopulations of CD56+ NK and NK-T peripheral blood lymphocytes identified by chemokine receptor expression repertoire. J Immunol 2001;166:6477–82. Oshima M, Maeda A, Ishioka S, Hiyama K, Yamakido M. Expression of C-C chemokines in bronchoalveolar lavage cells from patients with granulomatous lung diseases. Lung 1999;177:229–40. Konishi J, Yamazaki K, Yokouchi H, Shinagawa N, Iwabuchi K, Nishimura M. The characteristics of human NKT cells in lung cancer-CD1d independent cytotoxicity against lung cancer cells by NKT cells and decreased human NKT cell response in lung cancer patients. Hum Immunol 2004;65:1377–88. Terabe M, Berzofsky JA. The role of NKT cells in tumor immunity. Adv Cancer Res 2008;101:277–348. Seino K, Motohashi S, Fujisawa T, Nakayama T, Taniguchi M. Natural killer T cell-mediated antitumor immune responses and their clinical applications. Cancer Sci 2006;97:807–12. Molling JW, K¨ olgen W, van der Vliet HJ, Boomsma MF, Kruizenga H, Smorenburg CH, et al. Peripheral blood IFN-gsecreting Va24+Vb11+ NKT cell numbers are decreased in cancer
NKT cells in pulmonary disorders
55.
56.
57.
58.
patients independent of tumor type or tumor load. Int J Cancer 2005;116:87–93. Tahir SM, Cheng O, Shaulov A, Koezuka Y, Bubley GJ, Wilson SB, et al. Loss of IFN-g production by invariant NK T cells in advanced cancer. J Immunol 2001;167:4046–50. Motohashi S, Okamoto Y, Yoshino I, Nakayama T. Anti-tumor immune responses induced by iNKT cell-based immunotherapy for lung cancer and head and neck cancer. Clinical Immunology 2009 doi:10.1016/j.clim.2011.01.009. Taniguchi M, Tashiro T, Dashtsoodol N, Hongo N, Watarai H. The specialized iNKT cell system recognizes glycolipid antigens and bridges the innate and acquired immune systems with potential applications for cancer therapy. Int Immunol 2010;22:1–6. Motohashi S, Nagato K, Kunii N, Yamamoto H, Yamasaki K, Okita K, et al. A phase I-II study of alpha-galactosylceramidepulsed IL-2/GM-CSF-cultured peripheral blood mononuclear cells in patients with advanced and recurrent non-small cell lung cancer. J Immunol 2009;182:2492–501.
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59. Godfrey DI, Kronenberg M. Going both ways: immune regulation via CD1d-dependent NKT cells. J Clin Invest 2004;114:1379–88. 60. Sutherland JS, Jeffries DJ, Donkor S, Walther B, Hill PC, Adetifa IM, et al. High granulocyte/lymphocyte ratio and paucity of NKT cells defines TB disease in a TB-endemic setting. Tuberculosis 2009;89:398–404. 61. Montoya CJ, Cata˜ no JC, Ramirez Z, Rugeles MT, Wilson SB, Landay AL. Invariant NKT cells from HIV-1 or Mycobacterium tuberculosis-infected patients express an activated phenotype. Clin Immunol 2008;127:1–6. 62. Im JS, Kang TJ, Lee SB, Kim CH, Lee SH, Venkataswamy MM, et al. Alteration of the relative levels of iNKT cell subsets is associated with chronic mycobacterial infections. Clin Immunol 2008;127:214–24. 63. Lombardi V, Stock P, Singh AK, Kerzerho J, Yang W, Sullivan BA, et al. A CD1d-dependent antagonist inhibits the activation of invariant NKT cells and prevents development of allergeninduced airway hyperreactivity. J Immunol 2010;184:2107–15.