The Roles Of iNKT Cells In Asthma


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The Roles Of iNKT Cells In Asthma

  2. 2. Allergic Bronchial Asthma <ul><li>Inflammatory state: massive infiltration of eosinophils, lymphocytes and mast cells </li></ul><ul><li>Concomitant with various Th2 cytokines </li></ul>
  3. 3. <ul><li>Th2-biased responses </li></ul><ul><li>IL-13 : inflammation initiator, goblet cell hyperplasia, AHR, airway fibrosis </li></ul><ul><li>IL-4 : induction of Th2 responses??? </li></ul>
  4. 4. NKT Cells <ul><li>Discovery of NKT Cells </li></ul><ul><li>Definition of NKT Cells </li></ul><ul><li>NKT cell Role </li></ul><ul><li>Classification of NKT Cells </li></ul>
  5. 5. Discovery of NKT Cells <ul><li>Unexpected finding in examining the TCR repertoire of a series of suppressor T cell hybridomas </li></ul><ul><li>High frequency for a single TCR chain </li></ul>V  14 J  18 Imai et al., 1986 Koseki et al., 1989 Lantz and Bendelec, 1994 Makino et al., 1995 Cui et al., 1997
  6. 6. <ul><li>Presence of CD4-CD8- double negative (DN) cells expressing V  8 </li></ul><ul><li>CD44+, CD5+, NK1.1+ </li></ul><ul><li>Copious amounts of cytokine production </li></ul>Budd et al., 1987 Fowlkes et al., 1987 Ballas and Rasmussen, 1990 Sykes, 1990
  7. 7. <ul><li>V  8+, CD5high and CD44+ thymocyte hybridoma has the mRNA for the V  14 TCR chain </li></ul><ul><li>V  14+ cells in peripheral tissues express V  and NK1.1 </li></ul>Lantz and Bendelac. J.Exp.Med. 1994 Makino et al. Int. Immunol. 1995 Taniguchi et al. Proc. Natl.Acad.Sci. 1996
  8. 8. “ NKT Cell” <ul><li>What is an NKT cell? </li></ul><ul><li>Recognizes Ag presented by class-I like MHC molecule CD1d, NK1.1, CD5+high, CD44+high </li></ul><ul><li>Usually semi-invariant TCR V  14J  18 TCR  chain and most often V  8 TCR  chains </li></ul><ul><li>True TCR  T cells </li></ul><ul><li>NK markers </li></ul>
  9. 9. NKT Cell Role <ul><li>Rapid cytokine response from preformed mRNA </li></ul><ul><li>NKT’s IL-4 could promote Th2 responses & IgE production </li></ul><ul><li>NKT cells recognize bacterial glycosphingolipids </li></ul>Stetson et al. J.Exp.Med. 2003 IFN-  IL-4 Yoshimoto et al. Science.1995 Kinjo et al. Nature., 2005
  10. 10. Classification of NKT Cells Type I NKT Cells <ul><li>Invariant ab TCRs (Va14Ja18 in mice/Va24-Ja18 in humans) </li></ul><ul><li>CD1d restricted </li></ul>Type II NKT Cells <ul><li>Diverse TCR repertoire </li></ul><ul><li>CD1d restricted </li></ul>Type III NKT Cells <ul><li>MHC class I & II other than CD1d </li></ul>
  11. 11. Type I NKT Cells <ul><li>Three properties: </li></ul><ul><li>1. invariant V  14J  18 in mice/V  24J  18 in humans </li></ul><ul><li>2. limited repertoire of TCRs </li></ul><ul><li>3.  -GalCer recognition by CD1d </li></ul><ul><li>Other indefinite markers: NK1.1, Ly49 NK receptors, CD69, CD44 </li></ul>Kawano et al., 1997
  12. 12. Type I NKT Subsets <ul><li>Human DN type I NKT cells  Th1 cytokines </li></ul><ul><li>CD4+ type I NKT cells  Th1 & Th2 cytokines </li></ul>Gumperz et al., 2002 Lee et al., 2002a
  13. 13. iNKT Microbial Recognition <ul><li> -glucoronosylceramide (  -GalCer) </li></ul><ul><ul><li>Gram negative, LPS negative bacteria </li></ul></ul><ul><ul><li>Sphingomonas species </li></ul></ul><ul><ul><li>Ehrlichia species </li></ul></ul><ul><li>Phosphoinositolmannoside (PIM) </li></ul><ul><ul><li>Mycobacteria </li></ul></ul><ul><li>Leishmania glycoinositol phospholipids </li></ul><ul><li>Schistosome-derived glycoconjugate </li></ul>Terabe M et al. Adv.Canc.Res. 2008
  14. 14. iNKT Self-Antigen Recognition <ul><li>Glycosylphosphatidyl inositols </li></ul><ul><li>Phosphotidyl choline </li></ul><ul><li>Phosphotidyl inositol from soybeans </li></ul><ul><li>Phospholipid from pollen  a role in allergy??? </li></ul><ul><li>Glycosphingolipid isoglobotrihexosylceramide ( iGb3 ) </li></ul>Terabe M et al. Adv.Canc.Res. 2008
  15. 15. Asthma and NKT Cells <ul><li>Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. </li></ul><ul><li>1. AHR fails to develop </li></ul><ul><li>2. inability to produce Th2 responses </li></ul><ul><li>3. adoptive transfer reverses the failure of AHR development </li></ul>Akbari et al. Nat Med 2003
  16. 16. <ul><li>Invariant V alpha 14 NKT cells are required for allergen are required for allergen-induced airway inflammation and hyperreactivity in an experimental asthma model. </li></ul><ul><li>1. impaired AHR </li></ul><ul><li>2. adoptive transfer reconstitutes capacity to develop asthma </li></ul><ul><li>3. anti-CD treatment </li></ul>Lisbonne et al. J.Immunol. 2003
  17. 17. iNKT Cells in the Induction of AHR <ul><li>CD1d-/- mice fail to develop allergen-induced AHR </li></ul><ul><li>J  18-/- mice failed to develop AHR and showed reduced airway eosinophilia </li></ul><ul><li>Yet, allergen-specific Th2-driven responses still develop normally. </li></ul>Lisbonne et al. J.Immunol.2003 Akbari et al. Nat. Med. 2003
  18. 18. The Importance iNKT Cells in AHR Development <ul><li>Anergized iNKT cell treatment prevent development of allergen-induced AHR </li></ul><ul><li>Direct activation of pulmonary iNKT cells were sufficient to induce AHR </li></ul>Matsuda et al. Am.J.Respir.Cell.Mol.Biol.2005 Hachem et al. Eur.J.Immunol.2005 Morishima et al. Eur.J.Immunol. 2005 Meyer et al. Proc.Natl.Acad.Sci. 2006
  19. 19. <ul><li>AHR develops in absence of conventional CD4+ T cells and adaptive immunity, eosinophils, B cells </li></ul><ul><li>iNKT may not be required in all forms of AHR </li></ul><ul><li> 2-microglobulin-/- mice develops AHR normally </li></ul>Meyer et al. Annu.Rev.Med. 2008 Maeda et al. J.Immunol. 2004 Zhang et al. J.Exp. Med. 1996
  20. 20. iNKT Cells in Human Asthma <ul><li>Moderate-to-severe 14 persistent asthmatic patients, 5 stage II sarcoidosis, 6 healthy controls </li></ul><ul><li>Specimen: BALF </li></ul><ul><li>Staining of iNKT with CD1d tetramer loaded with  -GalCer and 6B11 mAb </li></ul>CD4+ Invariant T-Cell-Receptor+ Natural Killer T Cells in Bronchial Asthma Akbari O et al. NEJM. 2006
  21. 23. <ul><li>Staining of FITC 6B11 mAb </li></ul>Akbari O et al. NEJM. 2006
  22. 24. <ul><li>Red : phycoerythrin-conjugated CD4 </li></ul><ul><li>Blue : FITC 6B11 mAb </li></ul><ul><li>Pink : Overlay </li></ul>Akbari O et al. NEJM. 2006
  23. 25. Corticosteroid-treated Corticosteroid-untreated Akbari O et al. NEJM. 2006
  24. 26. <ul><li>RT-PCR </li></ul>Akbari O et al. NEJM. 2006
  25. 27. <ul><li>One subgroup of iNKT cells is selectively recruited or expanded in lungs of bronchial asthmatic patients. </li></ul>Akbari O et al. NEJM. 2006
  26. 28. Akbari O et al. NEJM. 2006
  27. 29. iNKT Cells in Human Asthma <ul><li>Specimen: peripheral V24 i NKT cells </li></ul>V alpha 24-invariant NKT cells from patients with allergic asthma express CCR9 at high frequency and induce Th2 bias of CD3+ T cells upon CD226 engagement Sen Y et al . J.Immunol. 2005
  28. 30. 87% Sen Y et al . J.Immunol. 2005
  29. 31. <ul><li>Highly increased frequency of asthmatic CCR9-expressing V24i NKT cells </li></ul>Sen Y et al . J.Immunol. 2005
  30. 32. CCR9 and V24 i NK T cell distribution Sen Y et al . J.Immunol. 2005
  31. 33. Asthmatic CCR9-expressing V24i NKT cells induced Th2 bias in CD3 T cells IL-4 IL-13 Sen Y et al . J.Immunol. 2005
  32. 34. IL-4 IL-13 Sen Y et al . J.Immunol. 2005
  33. 35. Confirm the function of different V24 i NKT cells IL-4 IL-13 Sen Y et al . J.Immunol. 2005
  34. 36. Transwell stimulations Sen Y et al . J.Immunol. 2005
  35. 37. CD226 expression in V24 i NKT cells Sen Y et al . J.Immunol. 2005
  36. 38. Sen Y et al . J.Immunol. 2005
  37. 39. CCR9 and CD226 activation Sen Y et al . J.Immunol. 2005
  38. 40. Sen Y et al . J.Immunol. 2005
  39. 41. Kay AB.NEJM. 2006 The Two Pathways
  40. 42. iNKT Cells in the Current Asthma Model Umetsu. Nature. 2006
  41. 43. iNKT Cells in Human Asthma <ul><li>Five of the seven reports confirm that the lungs of asthmatic patients contain more iNKT cells than normal controls </li></ul>Spinozzi et al. Immmunol. Allergy Clin. North Am. 2007 Pham-Thi N et al. JACI. 2006 Pham-Thi N et al. NEJM. 2006 Hamzaoui A et al. Mediat. Inflamm. 2006 Sen Y et al. J. Immunol. 2005
  42. 44. <ul><li>The other two reports concluded that iNKT cells are not increased in asthma </li></ul><ul><li>Up to 2% of the T cells in the lungs of asthmatic patients are iNKT cells </li></ul>Thomas SY et al. NEJM. 2006 Vijayanad P et al. NEJM. 2007
  43. 45. <ul><li>A new report suggesting the number of pulmonary iNKT cells may not relate to asthma severity and control. </li></ul><ul><li>5 severe, 8 well-controlled, 5 non-asthmatic patients </li></ul><ul><li>BALF analyzed by flow cytometry and stained with PBS57 and anti-CD3-Alexa750 </li></ul>Natural killer T Cells in the lungs of patients with asthma Umetsu et al. JACI. 2009
  44. 46. Adjusted percentages of iNKT cells/Tcells
  45. 47. Asthma Phenotypes Mild-moderate asthma Persistent severe asthma Th2 cell iNKT cell iNKT cell
  46. 48. Therapeutic Potentials <ul><li>Controversial </li></ul><ul><li>Glycolipid therapy </li></ul><ul><ul><li>IV administration  shift towards Th1 cytokine response </li></ul></ul><ul><ul><li>Intranasal administration  induces Th2 polarization and worsens eosinophilic infiltration and induces AHR </li></ul></ul>Oki and Miyake. Allergol.Internat. 2007
  47. 49. Thank You!