Programmed Cell Death Ligand 2 Regulates TH9 Differentiation and Induction of Chronic Airway Hyperreactivity

Overview

Journal J Allergy Clin Immunol

Specialty Allergy & Immunology

Date 2012 Nov 24

PMID 23174661

Citations 52

Authors

Jerome Kerzerho

Hadi Maazi

Anneliese O Speak

Natacha Szely

Vincent Lombardi

Bryant Khoo

Stacey Geryak

Jonathan Lam

Pejman Soroosh

Jacques Van Snick

Omid Akbari

Affiliations

Soon will be listed here.

Abstract

Background: Asthma is defined as a chronic inflammatory disease of the airways; however, the underlying physiologic and immunologic processes are not fully understood.

Objective: The aim of this study was to determine whether TH9 cells develop in vivo in a model of chronic airway hyperreactivity (AHR) and what factors control this development.

Method: We have developed a novel chronic allergen exposure model using the clinically relevant antigen Aspergillus fumigatus to determine the time kinetics of TH9 development in vivo.

Results: TH9 cells were detectable in the lungs after chronic allergen exposure. The number of TH9 cells directly correlated with the severity of AHR, and anti-IL-9 treatment decreased airway inflammation. Moreover, we have identified programmed cell death ligand (PD-L) 2 as a negative regulator of TH9 cell differentiation. Lack of PD-L2 was associated with significantly increased TGF-β and IL-1α levels in the lungs, enhanced pulmonary TH9 differentiation, and higher morbidity in the sensitized mice.

Conclusion: Our findings suggest that PD-L2 plays a pivotal role in the regulation of TH9 cell development in chronic AHR, providing novel strategies for modulating adaptive immunity during chronic allergic responses.

Citing Articles

Role of TGFβ-producing regulatory T cells in scleroderma and end-stage organ failure.

Lu K, Tsai K, Hu W Heliyon. 2024; 10(15):e35590.

PMID: 39170360 PMC: 11336735. DOI: 10.1016/j.heliyon.2024.e35590.

CB2 stimulation of adipose resident ILC2s orchestrates immune balance and ameliorates type 2 diabetes mellitus.

Shafiei-Jahani P, Yan S, Kazemi M, Li X, Akbari A, Sakano K Cell Rep. 2024; 43(7):114434.

PMID: 38963763 PMC: 11317174. DOI: 10.1016/j.celrep.2024.114434.

The Differentially Expressed Genes Responsible for the Development of T Helper 9 Cells From T Helper 2 Cells in Various Disease States: Immuno-Interactomics Study.

Khokhar M, Purohit P, Gadwal A, Tomo S, Bajpai N, Shukla R JMIR Bioinform Biotechnol. 2024; 4:e42421.

PMID: 38935935 PMC: 11135241. DOI: 10.2196/42421.

T-helper cells and their cytokines in pathogenesis and treatment of asthma.

Ji T, Li H Front Immunol. 2023; 14:1149203.

PMID: 37377958 PMC: 10291091. DOI: 10.3389/fimmu.2023.1149203.

The Emerging Role of IL-9 in the Anticancer Effects of Anti-PD-1 Therapy.

Vinokurova D, Apetoh L Biomolecules. 2023; 13(4).

PMID: 37189417 PMC: 10136177. DOI: 10.3390/biom13040670.

References

Hultner L, Moeller J . Mast cell growth-enhancing activity (MEA) stimulates interleukin 6 production in a mouse bone marrow-derived mast cell line and a malignant subline. Exp Hematol. 1990; 18(8):873-7. View

Keir M, Liang S, Guleria I, Latchman Y, Qipo A, Albacker L . Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006; 203(4):883-95. PMC: 2118286. DOI: 10.1084/jem.20051776. View

Radhakrishnan S, Iijima K, Kobayashi T, Kita H, Pease L . Dendritic cells activated by cross-linking B7-DC (PD-L2) block inflammatory airway disease. J Allergy Clin Immunol. 2005; 116(3):668-74. DOI: 10.1016/j.jaci.2005.04.038. View

Doherty T, Soroosh P, Khorram N, Fukuyama S, Rosenthal P, Cho J . The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling. Nat Med. 2011; 17(5):596-603. PMC: 3097134. DOI: 10.1038/nm.2356. View

Lombardi V, Speak A, Kerzerho J, Szely N, Akbari O . CD8α⁺β⁻ and CD8α⁺β⁺ plasmacytoid dendritic cells induce Foxp3⁺ regulatory T cells and prevent the induction of airway hyper-reactivity. Mucosal Immunol. 2012; 5(4):432-43. PMC: 3378819. DOI: 10.1038/mi.2012.20. View

Gessner A, Blum H, Rollinghoff M . Differential regulation of IL-9-expression after infection with Leishmania major in susceptible and resistant mice. Immunobiology. 1993; 189(5):419-35. DOI: 10.1016/S0171-2985(11)80414-6. View

Uyttenhove C, Simpson R, Van Snick J . Functional and structural characterization of P40, a mouse glycoprotein with T-cell growth factor activity. Proc Natl Acad Sci U S A. 1988; 85(18):6934-8. PMC: 282093. DOI: 10.1073/pnas.85.18.6934. View

Temann U, Geba G, Rankin J, Flavell R . Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J Exp Med. 1998; 188(7):1307-20. PMC: 2212487. DOI: 10.1084/jem.188.7.1307. View

Messal N, Serriari N, Pastor S, Nunes J, Olive D . PD-L2 is expressed on activated human T cells and regulates their function. Mol Immunol. 2011; 48(15-16):2214-9. DOI: 10.1016/j.molimm.2011.06.436. View

10.

Renauld J, Vink A, Louahed J, Van Snick J . Interleukin-9 is a major anti-apoptotic factor for thymic lymphomas. Blood. 1995; 85(5):1300-5. View

11.

Veldhoen M, Uyttenhove C, Van Snick J, Helmby H, Westendorf A, Buer J . Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol. 2008; 9(12):1341-6. DOI: 10.1038/ni.1659. View

12.

Hultner L, Druez C, Moeller J, Uyttenhove C, Schmitt E, Rude E . Mast cell growth-enhancing activity (MEA) is structurally related and functionally identical to the novel mouse T cell growth factor P40/TCGFIII (interleukin 9). Eur J Immunol. 1990; 20(6):1413-6. DOI: 10.1002/eji.1830200632. View

13.

Mizutani N, Goshima H, Nabe T, Yoshino S . Complement C3a-induced IL-17 plays a critical role in an IgE-mediated late-phase asthmatic response and airway hyperresponsiveness via neutrophilic inflammation in mice. J Immunol. 2012; 188(11):5694-705. DOI: 10.4049/jimmunol.1103176. View

14.

Wong M, Ye J, Alonso M, Landrigan A, Cheung R, Engleman E . Regulation of human Th9 differentiation by type I interferons and IL-21. Immunol Cell Biol. 2010; 88(6):624-31. PMC: 3090036. DOI: 10.1038/icb.2010.53. View

15.

Shimbara A, Christodoulopoulos P, Olivenstein R, Nakamura Y, Levitt R, Nicolaides N . IL-9 and its receptor in allergic and nonallergic lung disease: increased expression in asthma. J Allergy Clin Immunol. 2000; 105(1 Pt 1):108-15. DOI: 10.1016/s0091-6749(00)90185-4. View

16.

Wilhelm C, Turner J, Van Snick J, Stockinger B . The many lives of IL-9: a question of survival?. Nat Immunol. 2012; 13(7):637-41. DOI: 10.1038/ni.2303. View

17.

Richard M, Grencis R, Humphreys N, Renauld J, Van Snick J . Anti-IL-9 vaccination prevents worm expulsion and blood eosinophilia in Trichuris muris-infected mice. Proc Natl Acad Sci U S A. 2000; 97(2):767-72. PMC: 15405. DOI: 10.1073/pnas.97.2.767. View

18.

Lombardi V, Stock P, Singh A, Kerzerho J, Yang W, Sullivan B . A CD1d-dependent antagonist inhibits the activation of invariant NKT cells and prevents development of allergen-induced airway hyperreactivity. J Immunol. 2010; 184(4):2107-15. PMC: 2845715. DOI: 10.4049/jimmunol.0901208. View

19.

Temann U, Ray P, Flavell R . Pulmonary overexpression of IL-9 induces Th2 cytokine expression, leading to immune pathology. J Clin Invest. 2002; 109(1):29-39. PMC: 150821. DOI: 10.1172/JCI13696. View

20.

Louahed J, Toda M, Jen J, Hamid Q, Renauld J, Levitt R . Interleukin-9 upregulates mucus expression in the airways. Am J Respir Cell Mol Biol. 2000; 22(6):649-56. DOI: 10.1165/ajrcmb.22.6.3927. View