A CD1d-dependent Antagonist Inhibits the Activation of Invariant NKT Cells and Prevents Development of Allergen-induced Airway Hyperreactivity

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2010 Jan 20

PMID 20083656

Citations 24

Authors

Vincent Lombardi

Philippe Stock

Abinav K Singh

Jerome Kerzerho

Wen Yang

Barbara A Sullivan

Xiangming Li

Takayuki Shiratsuchi

Nathan E Hnatiuk

Amy R Howell

Karl O A Yu

Steven A Porcelli

Moriya Tsuji

Mitchell Kronenberg

S Brian Wilson

Omid Akbari

Affiliations

Soon will be listed here.

Abstract

The prevalence of asthma continues to increase in westernized countries, and optimal treatment remains a significant therapeutic challenge. Recently, CD1d-restricted invariant NKT (iNKT) cells were found to play a critical role in the induction of airway hyperreactivity (AHR) in animal models and are associated with asthma in humans. To test whether iNKT cell-targeted therapy could be used to treat allergen-induced airway disease, mice were sensitized with OVA and treated with di-palmitoyl-phosphatidyl-ethanolamine polyethylene glycol (DPPE-PEG), a CD1d-binding lipid antagonist. A single dose of DPPE-PEG prevented the development of AHR and pulmonary infiltration of lymphocytes upon OVA challenge, but had no effect on the development of OVA-specific Th2 responses. In addition, DPPE-PEG completely prevented the development of AHR after administration of alpha-galactosylceramide (alpha-GalCer) intranasally. Furthermore, we demonstrate that DPPE-PEG acts as antagonist to alpha-GalCer and competes with alpha-GalCer for binding to CD1d. Finally, we show that DPPE-PEG completely inhibits the alpha-GalCer-induced phosphorylation of ERK tyrosine kinase in iNKT cells, suggesting that DPPE-PEG specifically blocks TCR signaling and thus activation of iNKT cells. Because iNKT cells play a critical role in the development of AHR, the inhibition of iNKT activation by DPPE-PEG suggests a novel approach to treat iNKT cell-mediated diseases such as asthma.

Citing Articles

Alpha-galactosylceramide pre-treatment attenuates clinical symptoms of LPS-induced acute neuroinflammation by converting pathogenic iNKT cells to anti-inflammatory iNKT10 cells in the brain.

Kim T, Park H, Lee S, Park Y, Van Kaer L, Hong S Inflamm Res. 2024; 73(9):1511-1527.

PMID: 39028491 DOI: 10.1007/s00011-024-01915-3.

CD1-mediated immune responses in mucosal tissues: molecular mechanisms underlying lipid antigen presentation system.

Kim S, Cho S, Kim J Exp Mol Med. 2023; 55(9):1858-1871.

PMID: 37696897 PMC: 10545705. DOI: 10.1038/s12276-023-01053-6.

Choline chloride attenuates the allergic airway disease by inhibiting the lysophosphatidylcholine induced response in mouse model.

Bansal P, Singh N, Joshi J, Arora N, Gaur S Curr Res Pharmacol Drug Discov. 2022; 3:100109.

PMID: 35707627 PMC: 9188963. DOI: 10.1016/j.crphar.2022.100109.

Repeated α-GalCer Administration Induces a Type 2 Cytokine-Biased iNKT Cell Response and Exacerbates Atopic Skin Inflammation in Vα14 NC/Nga Mice.

Park H, Kim T, Park Y, Lee S, Jeon J, Park S Biomedicines. 2021; 9(11).

PMID: 34829848 PMC: 8615984. DOI: 10.3390/biomedicines9111619.

α-Lactosylceramide Protects Against iNKT-Mediated Murine Airway Hyperreactivity and Liver Injury Through Competitive Inhibition of Cd1d Binding.

Lai A, Chi P, Thio C, Han Y, Kao H, Hsieh H Front Chem. 2019; 7:811.

PMID: 31850305 PMC: 6893574. DOI: 10.3389/fchem.2019.00811.

References

Hamzaoui A, Cheik Rouhou S, Grairi H, Abid H, Ammar J, Chelbi H . NKT cells in the induced sputum of severe asthmatics. Mediators Inflamm. 2006; 2006(2):71214. PMC: 1592585. DOI: 10.1155/MI/2006/71214. View

Burrows B, Martinez F, Halonen M, BARBEE R, Cline M . Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med. 1989; 320(5):271-7. DOI: 10.1056/NEJM198902023200502. View

Kim E, Battaile J, Patel A, You Y, Agapov E, Grayson M . Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat Med. 2008; 14(6):633-40. PMC: 2575848. DOI: 10.1038/nm1770. View

Matangkasombut P, Pichavant M, Yasumi T, Hendricks C, Savage P, DeKruyff R . Direct activation of natural killer T cells induces airway hyperreactivity in nonhuman primates. J Allergy Clin Immunol. 2008; 121(5):1287-9. PMC: 2655765. DOI: 10.1016/j.jaci.2008.02.006. View

Arreaza G, Cameron M, Jaramillo A, Gill B, Hardy D, Laupland K . Neonatal activation of CD28 signaling overcomes T cell anergy and prevents autoimmune diabetes by an IL-4-dependent mechanism. J Clin Invest. 1997; 100(9):2243-53. PMC: 508420. DOI: 10.1172/JCI119762. View

Kim J, Kim D, Chang W, Hong C, Park S, Kim S . Asthma is induced by intranasal coadministration of allergen and natural killer T-cell ligand in a mouse model. J Allergy Clin Immunol. 2004; 114(6):1332-8. DOI: 10.1016/j.jaci.2004.09.004. View

Kronenberg M, Gapin L . The unconventional lifestyle of NKT cells. Nat Rev Immunol. 2002; 2(8):557-68. DOI: 10.1038/nri854. View

Nieuwenhuis E, Gillessen S, Scheper R, Exley M, Taniguchi M, Balk S . CD1d and CD1d-restricted iNKT-cells play a pivotal role in contact hypersensitivity. Exp Dermatol. 2005; 14(4):250-8. DOI: 10.1111/j.0906-6705.2005.00289.x. View

Russano A, Agea E, Corazzi L, Postle A, De Libero G, Porcelli S . Recognition of pollen-derived phosphatidyl-ethanolamine by human CD1d-restricted gamma delta T cells. J Allergy Clin Immunol. 2006; 117(5):1178-84. DOI: 10.1016/j.jaci.2006.01.001. View

10.

Robinson D, Hamid Q, Ying S, Tsicopoulos A, Barkans J, Bentley A . Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992; 326(5):298-304. DOI: 10.1056/NEJM199201303260504. View

11.

Stotz S, Bolliger L, Carbone F, Palmer E . T cell receptor (TCR) antagonism without a negative signal: evidence from T cell hybridomas expressing two independent TCRs. J Exp Med. 1999; 189(2):253-64. PMC: 2192976. DOI: 10.1084/jem.189.2.253. View

12.

Kamps J, Scherphof G . Biodistribution and uptake of liposomes in vivo. Methods Enzymol. 2004; 387:257-66. DOI: 10.1016/S0076-6879(04)87016-2. View

13.

Wilson S, Kent S, Patton K, Orban T, Jackson R, EXLEY M . Extreme Th1 bias of invariant Valpha24JalphaQ T cells in type 1 diabetes. Nature. 1998; 391(6663):177-81. DOI: 10.1038/34419. View

14.

Jin N, Miyahara N, Roark C, French J, Aydintug M, Matsuda J . Airway hyperresponsiveness through synergy of gammadelta} T cells and NKT cells. J Immunol. 2007; 179(5):2961-8. PMC: 4480876. DOI: 10.4049/jimmunol.179.5.2961. View

15.

Pichavant M, Goya S, Meyer E, Johnston R, Kim H, Matangkasombut P . Ozone exposure in a mouse model induces airway hyperreactivity that requires the presence of natural killer T cells and IL-17. J Exp Med. 2008; 205(2):385-93. PMC: 2271004. DOI: 10.1084/jem.20071507. View

16.

Yu K, Im J, Illarionov P, Ndonye R, Howell A, Besra G . Production and characterization of monoclonal antibodies against complexes of the NKT cell ligand alpha-galactosylceramide bound to mouse CD1d. J Immunol Methods. 2007; 323(1):11-23. PMC: 1939826. DOI: 10.1016/j.jim.2007.03.006. View

17.

Sidobre S, Kronenberg M . CD1 tetramers: a powerful tool for the analysis of glycolipid-reactive T cells. J Immunol Methods. 2002; 268(1):107-21. DOI: 10.1016/s0022-1759(02)00204-1. View

18.

Kersh E, Kersh G, Allen P . Partially phosphorylated T cell receptor zeta molecules can inhibit T cell activation. J Exp Med. 1999; 190(11):1627-36. PMC: 2195733. DOI: 10.1084/jem.190.11.1627. View

19.

Illi S, von Mutius E, Lau S, Nickel R, Niggemann B, Sommerfeld C . The pattern of atopic sensitization is associated with the development of asthma in childhood. J Allergy Clin Immunol. 2001; 108(5):709-14. DOI: 10.1067/mai.2001.118786. View

20.

Sen Y, Yongyi B, Yuling H, Luokun X, Li H, Jie X . 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. J Immunol. 2005; 175(8):4914-26. DOI: 10.4049/jimmunol.175.8.4914. View