Programmed cell death ligand 2 regulates TH9 differentiation and induction of chronic airway hyperreactivity

Kerzerho, Jérôme; Maazi, Hadi; Speak, Anneliese O.; Szely, Natacha; Lombardi, Vincent; Khoo, Bryant; Geryak, Stacey; Lam, Jonathan; Soroosh, Pejman; Snick, Jacques Van; Akbari, Omid

doi:10.1016/j.jaci.2012.09.027

Cited by 91 publications

(70 citation statements)

References 66 publications

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“…This highlights the need for well-defined asthma models specifically suited for addressing disease mechanisms or for evaluating existing and novel therapies. Chronic sensitisation protocols have been reported to result in models of pronounced Th2-type disease [10,11,12,15], more mixed types of diseases [14,30,31], and even dexamethasone insensitive disease [32]. Our cat allergen-induced asthma model exhibits characteristics of Th17/neutrophilic asthma with increased neutrophil numbers in BAL and increased levels of IL-17a in lung tissue.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, both improved chronic OVA protocols [10] and protocols with relevant inhaled allergens (e.g. dust mite, pollen and moulds [11,12,13,14]) have been developed. Chronic asthma models have been employed in a number of studies of disease and treatment mechanisms [12,14,15,16,17,18], but there is still a need for improved models of allergy and asthma induced by allergens relevant for human disease.…”

Section: Introductionmentioning

confidence: 99%

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Development of a Mouse Model for Chronic Cat Allergen-Induced Asthma

Grundström

Saarne

Kemi³

et al. 2014

Int Arch Allergy Immunol

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Background: Allergic asthma is a chronic inflammatory airway disease caused by exposure to airborne allergens. In order to develop novel therapies for allergic asthma, models that are relevant to human disease are needed. Methods: Female BALB/c mice were presensitised subcutaneously with alum-adsorbed recombinant cat allergen Fel d 1, followed by intranasal challenges with cat dander extract spiked with recombinant Fel d 1 for 7 weeks. For reference, mice were presensitised and challenged with ovalbumin following the same protocol. Airway hyperresponsiveness, serum antibodies, airway inflammation and cell infiltration, and cytokines in lung tissue and bronchoalveolar lavage were measured. Results: Mice presensitised with recombinant Fel d 1 and challenged with cat dander extract or presensitised and challenged with ovalbumin showed airway hyperresponsiveness in response to metacholine. Mice of the cat allergen model showed influx of neutrophils, eosinophils and lymphocytes in bronchoalveolar lavage, combined with increased levels of IL-17a and increased IL-4 mRNA expression in lung tissue. In contrast, mice sensitised and challenged with ovalbumin showed a predominant influx of eosinophils in bronchoalveolar lavage and had an increased expression of IL-5 in lung tissue. Both protocols induced features of lung tissue remodelling and allergen-specific antibody responses. Conclusions: The presented mouse model for cat allergen-induced asthma exhibits hallmarks of chronic allergic asthma, like airway hyperresponsiveness, a mixed neutrophilic/eosinophilic infiltration in bronchoalveolar lavage, expression of IL-17a and signs of remodelling in lung tissue. The model will provide a relevant platform for the development of novel treatment strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of a Mouse Model for Chronic Cat Allergen-Induced Asthma

Grundström

Saarne

Kemi³

et al. 2014

Int Arch Allergy Immunol

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“…Th9 cells play a pivotal role in health and disease. Th9 cells have been shown to exacerbate the airway allergic immune response by recruiting eosinophils and mast cells to the lungs, increasing mucus production, and production of serum IgE (11,12). Th9 cells further contribute to the host-immune reaction against helminth infections and tumors (7,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23).…”

Section: Cd4mentioning

confidence: 99%

Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells

Singh

Zhou

Shi

et al. 2016

Journal of Biological Chemistry

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CD4؉ T helper 9 (Th9) cells are a newly discovered Th cell subset that produce the pleiotropic cytokine IL-9. Th9 cells can protect against tumors and provide resistance against helminth infections. Given their pivotal role in the adaptive immune system, understanding Th9 cell development and the regulation of IL-9 production could open novel immunotherapeutic opportunities. The Na ؉ /H ؉ exchanger 1 (NHE1; gene name Slc9␣1)) is critically important for regulating intracellular pH (pH i ), cell volume, migration, and cell survival. The pH i influences cytokine secretion, activities of membrane-associated enzymes, ion transport, and other effector signaling molecules such as ATP and Ca 2؉ levels. However, whether NHE1 regulates Th9 cell development or IL-9 secretion has not yet been defined. The present study explored the role of NHE1 in Th9 cell development and function. Th cell subsets were characterized by flow cytometry and pH i was measured using 2,7-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein-acetoxymethyl ester (BCECF-AM) dye. NHE1 functional activity was estimated from the rate of realkalinization following an ammonium pulse. Surprisingly, in Th9 cells pH i and NHE1 activity were significantly higher than in all other Th cell subsets (Th1/Th2/Th17 and induced regulatory T cells (iTregs)). NHE1 transcript levels and protein abundance were significantly higher in Th9 cells than in other Th cell subsets. Inhibition of NHE1 by siRNA-NHE1 or with cariporide in Th9 cells down-regulated IL-9 and ATP production. NHE1 activity, Th9 cell development, and IL-9 production were further blunted by pharmacological inhibition of protein kinase Akt1/Akt2. Our findings reveal that Akt1/Akt2 control of NHE1 could be an important physiological regulator of Th9 cell differentiation, IL-9 secretion, and ATP production. CD4ϩ T cells participate in the regulation of the immune response during infections, autoimmunity, and cancer. CD4 ϩ T cells are an important and essential arm of the adaptive immune system (1). CD4 ϩ T cells can be divided into various subtypes based upon their cytokine secretion: T helper 1 (Th1) 4 cells produce IFN-␥ (1, 2), Th2 cells produce IL-4, IL-5, and IL-13 (3), Th17 cells produce IL-17 (4 -6), Th9 cells produce IL-9 (7-9), and suppressive regulatory T cells (Tregs) produce TGF-␤ and IL-10 (10). A great deal of experimental effort has been dedicated to decipher the development and function of various Th cell subsets. However, Th9 cell development and function remain incompletely understood.Th9 cells are a recently characterized Th cell subset recognized by their potent production of IL-9. Th9 cells play a pivotal role in health and disease. Th9 cells have been shown to exacerbate the airway allergic immune response by recruiting eosinophils and mast cells to the lungs, increasing mucus production, and production of serum IgE (11, 12). Th9 cells further contribute to the host-immune reaction against helminth infections and tumors (7, 13-23). The development and function of Th9 cells are regulated ...

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“…A recent study by Kerzerho and colleagues indicated that programmed cell death ligand 2 (PD-L2) downregulates the differentiation of Th9 cells in an Aspergillus fumigatus-induced model of chronic airway hyper-responsiveness (AHR). Blocking PD-L2 results in an increase of IL-9 production albeit no effect on IL-4 produced by Th2 cells [32].…”

Section: Co-stimulatory Factorsmentioning

confidence: 98%

“…Exposure of mice to house dust mite results in the rapid accumulation Th9 cells that produce IL-9 in the absence of IL-13, IL-10 and IFN-γ, which directly correlated with the severity of AHR and anti-IL-9 treatment decreased airway inflammation [26]. A recent study of chronic AHR induced by intranasal Aspergillus fumigatus lysates reveals that Th9 cells did not coexpress IL-4, IL-10, and IL-13 [32] …”

Section: Asthmaand Airway Hyper-responsiveness (Ahr)mentioning

confidence: 99%

Differentiation, Regulation and Function of Th9 Cells

Jia

2014

Advances in Experimental Medicine and Biology

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Naïve CD4(+) T cells are activated and differentiate to distinct lineages of T helper (Th) cells, which are involved in physiological and pathological processes by obtaining the potential to produce different lineage-specific cytokines that mediate adaptive immunity. In the past decade, our knowledge of Th cells has been significantly expanded with the findings of new lineages. Interleukin (IL)-9 producing T cells are recently identified. In consideration of the ability to preferentially secret IL-9, these cells are termed Th9 cells. Given the multiple function of IL-9, Th9 cells participate in the lesion of many diseases, such as allergic inflammation, tumor, and parasitosis. In this chapter, we will focus on the cytokines, co-stimulatory factors, and transcriptional signaling pathways, which regulate Th9 cells development as well as stability, plasticity, and the multiple roles of Th9 cells in vivo.

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Programmed cell death ligand 2 regulates TH9 differentiation and induction of chronic airway hyperreactivity

Cited by 91 publications

References 66 publications

Development of a Mouse Model for Chronic Cat Allergen-Induced Asthma

Development of a Mouse Model for Chronic Cat Allergen-Induced Asthma

Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells

Differentiation, Regulation and Function of Th9 Cells

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