The Roles Of iNKT Cells In Asthma
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The Roles Of iNKT Cells In Asthma






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The Roles Of iNKT Cells In Asthma The Roles Of iNKT Cells In Asthma Presentation Transcript

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