the roles of inkt cells in asthma
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พญ.รั�งสิ�มา เหรั ยญตรัะกู�ลIMMUNOLOGY DIVISION
DEPARTMENT OF MICROBIOLOGYFACULTY OF MEDICINE
CHULALONGKORN UNIVERSITY
The Role of iNKT Cells in Asthma
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Allergic Bronchial Asthma
Inflammatory state: massive infiltration of eosinophils, lymphocytes and mast cells
Concomitant with various Th2 cytokines
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Th2-biased responses
IL-13: inflammation initiator, goblet cell hyperplasia, AHR, airway fibrosis
IL-4: induction of Th2 responses???
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NKT Cells
Discovery of NKT CellsDefinition of NKT CellsNKT cell RoleClassification of NKT Cells
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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
V14 J18
Imai et al., 1986Koseki et al., 1989
Lantz and Bendelec, 1994Makino et al., 1995Cui et al., 1997
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Presence of CD4-CD8- double negative (DN) cells expressing V8
CD44+, CD5+, NK1.1+Copious amounts of cytokine production
Budd et al., 1987Fowlkes et al., 1987Ballas and Rasmussen, 1990Sykes, 1990
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V8+, CD5high and CD44+ thymocyte hybridoma has the mRNA for the V14 TCR chain
V14+ cells in peripheral tissues express V and NK1.1
Lantz and Bendelac. J.Exp.Med. 1994
Makino et al. Int. Immunol. 1995Taniguchi et al. Proc. Natl.Acad.Sci. 1996
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“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 V14J18 TCR chain and most often V8 TCR chains
•True TCR T cells•NK markers
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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
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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
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Type I NKT Cells
Three properties:1. invariant V14J18 in mice/V24J18 in
humans2. limited repertoire of TCRs3. -GalCer recognition by CD1d
Other indefinite markers: NK1.1, Ly49 NK receptors, CD69, CD44
Kawano et al., 1997
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Type I NKT Subsets
Human DN type I NKT cells Th1 cytokinesCD4+ type I NKT cells Th1 & Th2
cytokinesGumperz et al., 2002Lee et al., 2002a
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iNKT Microbial Recognition
-glucoronosylceramide (-GalCer) Gram negative, LPS negative bacteria Sphingomonas species Ehrlichia species
Phosphoinositolmannoside (PIM) Mycobacteria
Leishmania glycoinositol phospholipidsSchistosome-derived glycoconjugate
Terabe M et al. Adv.Canc.Res. 2008
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iNKT Self-Antigen Recognition
Glycosylphosphatidyl inositolsPhosphotidyl cholinePhosphotidyl inositol from soybeansPhospholipid from pollen a role in
allergy???Glycosphingolipid isoglobotrihexosylceramide
(iGb3)
Terabe M et al. Adv.Canc.Res. 2008
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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 develop2. inability to produce Th2 responses3. adoptive transfer reverses the failure of
AHR development
Akbari et al. Nat Med 2003
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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 AHR2. adoptive transfer reconstitutes capacity to
develop asthma3. anti-CD treatment
Lisbonne et al. J.Immunol. 2003
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iNKT Cells in the Induction of AHR
CD1d-/- mice fail to develop allergen-induced AHR
J18-/- 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
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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.2005Hachem et al. Eur.J.Immunol.2005Morishima et al. Eur.J.Immunol. 2005
Meyer et al. Proc.Natl.Acad.Sci. 2006
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AHR develops in absence of conventional CD4+ T cells and adaptive immunity, eosinophils, B cells
iNKT may not be required in all forms of AHR2-microglobulin-/- mice develops AHR
normally
Meyer et al. Annu.Rev.Med. 2008
Maeda et al. J.Immunol. 2004Zhang et al. J.Exp. Med. 1996
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iNKT Cells in Human Asthma
Moderate-to-severe 14 persistent asthmatic patients, 5 stage II sarcoidosis, 6 healthy controls
Specimen: BALFStaining 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
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Staining of FITC 6B11 mAb
Akbari O et al. NEJM. 2006
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Red: phycoerythrin-conjugated CD4Blue: FITC 6B11 mAbPink: Overlay Akbari O et al. NEJM. 2006
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Corticosteroid-treatedCorticosteroid-untreated
Akbari O et al. NEJM. 2006
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RT-PCR
Akbari O et al. NEJM. 2006
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One subgroup of iNKT cells is selectively recruited or expanded in lungs of bronchial asthmatic patients.
Akbari O et al. NEJM. 2006
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Akbari O et al. NEJM. 2006
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iNKT Cells in Human Asthma
Specimen: peripheral V24i 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
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87%
Sen Y et al . J.Immunol. 2005
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Highly increased frequency of asthmatic CCR9-expressing V24i NKT cells
Sen Y et al . J.Immunol. 2005
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CCR9 and V24i NK T cell distribution
Sen Y et al . J.Immunol. 2005
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Asthmatic CCR9-expressing V24i NKT cells induced Th2 biasin CD3 T cells
IL-4 IL-13
Sen Y et al . J.Immunol. 2005
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IL-4 IL-13
Sen Y et al . J.Immunol. 2005
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Confirm the function of different V24i NKT cells
IL-4
IL-13
Sen Y et al . J.Immunol. 2005
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Transwell stimulationsSen Y et al . J.Immunol. 2005
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CD226 expression in V24i NKT cells
Sen Y et al . J.Immunol. 2005
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Sen Y et al . J.Immunol. 2005
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CCR9 and CD226 activation
Sen Y et al . J.Immunol. 2005
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Sen Y et al . J.Immunol. 2005
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Kay AB.NEJM. 2006
The Two Pathways
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iNKT Cells in the Current Asthma Model
Umetsu. Nature. 2006
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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. 2007Pham-Thi N et al. JACI. 2006Pham-Thi N et al. NEJM. 2006Hamzaoui A et al. Mediat. Inflamm. 2006Sen Y et al. J. Immunol. 2005
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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. 2006Vijayanad P et al. NEJM. 2007
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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
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Adjusted percentages of iNKT cells/Tcells
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Asthma Phenotypes
Mild-moderate asthma
Persistent severe asthma
Th2 cell iNKT cell
iNKT cell
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Therapeutic Potentials
ControversialGlycolipid 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
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Thank You!