Activin A and TGF-β promote TH9 cell–mediated pulmonary allergic pathology

doi:10.1016/j.jaci.2011.12.965

Journal of Allergy and Clinical Immunology

Volume 129, Issue 4, April 2012, Pages 1000-1010.e3

https://doi.org/10.1016/j.jaci.2011.12.965 Get rights and content

Background

IL-9–secreting (T_H9) T cells are thought to represent a distinct T-cell subset. However, evidence for their functionality in disease is uncertain.

Objective

To define a functional phenotype for T_H9-driven pathology in vivo.

Methods

We used fluorescence-activated cell sorting to identify circulating T_H9 cells in atopic and nonatopic subjects. In mice we utilized a model of allergic airways disease induced by house dust mite to determine T_H9 cell function in vivo and the role of activin A in T_H9 generation.

Results

Allergic patients have elevated T_H9 cell numbers in comparison to nonatopic donors, which correlates with elevated IgE levels. In a murine model, allergen challenge with house dust mite leads to rapid T_H9 differentiation and proliferation, with much faster kinetics than for T_H2 cell differentiation, resulting in the specific recruitment and activation of mast cells. The TGF-β superfamily member activin A replicates the function of TGF-β1 in driving the in vitro generation of T_H9 cells. Importantly, the in vivo inhibition of T_H9 differentiation induced by allergen was achieved only when activin A and TGF-β were blocked in conjunction but not alone, resulting in reduced airway hyperreactivity and collagen deposition. Conversely, adoptive transfer of T_H9 cells results in enhanced pathology.

Conclusion

Our data identify a distinct functional role for T_H9 cells and outline a novel pathway for their generation in vitro and in vivo. Functionally, T_H9 cells promote allergic responses resulting in enhanced pathology mediated by the specific recruitment and activation of mast cells in the lungs.

Section snippets

Mice

BALB/c and severe combined immunodeficiency mice (6-8 weeks) were purchased from Charles River (Morgate, United Kingdom [UK]). All experiments were performed in accordance with UK Home Office guidelines.

Induction and analysis of allergic airway inflammation

Mice received 15 μg of house dust mite (HDM) extract (Dermatophagoides pteronyssinus in saline; Greer Laboratories, Lenoir, NC) or saline intranasally 3 days a week for 1 or 3 weeks. In adoptive transfer experiments, 1 × 10⁶ in vitro generated T_H9 cells (more than 90% CD4⁺IL-9⁺IL-13⁻IFN-γ⁻) were

T_H9 cells are generated in the lungs following exposure to allergen and are associated with atopy in patients

PBMCs isolated from asthmatic children generate greater numbers of T_H9 cells in vitro when compared with nonasthmatic controls.⁹ However, direct evidence for the existence of T_H9 cells during an allergic response in vivo is lacking. In order to directly evaluate the T_H9 subset in human subjects, we isolated PBMCs from allergic or nonallergic donors, and quantified them by flow. We found significantly higher numbers of circulating T_H9 cells, defined as CD4⁺IL-9⁺IL-13⁻IFN-γ⁻, in allergic donors

Discussion

Asthma is a complex heterogeneous disease thought to occur as a consequence of aberrant T_H2 immunity to innocuous environmental particles such as dust and animal dander. However, it is clear that a range of other T cells contribute to disease pathology, which might account for this heterogeneity.²² We demonstrate here that T_H9 cells are present in human peripheral blood, since previous studies have shown IL-9 levels only in plasma or T_H9 cells generated in vitro from PBMCs. Importantly,

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Citation Excerpt :
In contrast with TH2A cells, TH9 cells lack expression of IL-4 and IL-13.85 In mice, adoptive transfer of TH9 cells is sufficient to induce AHR to a similar extent as TH2 cells.88,89 Importantly, AHR after the adoptive transfer of TH9, but not TH2 cells, is steroid-resistant in mice.90
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The role of main TCD4+ lymphocyte subsets including T helper 1 (Th1), Th2, Th17, and T regulatory cells in transplantation has already been described; however, the implication of newly defined lineages such as Th22, Th9, and T follicular helper cells in alloimmune responses remain to be elucidated. In addition to the low number of studies, most evidence about the role of these cells in transplantation has been obtained from experimental studies, which might be insufficient or irrelevant for clinical interpretations. In the present article, we have reviewed the studies that have investigated the role of Th9 and its principal cytokine interleukin-9 (IL-9) in allograft rejection and tolerance induction. However, the findings tend to be controversial since some investigations demonstrate positive effects of Th9 on transplantation outcomes whereas others are suggestive of its detrimental influences. A similar challenge is presented by IL-9 as both advantages and disadvantages of IL-9 expression in allografts have been reported. Moreover, different organs appear to be affected in different ways by Th9 cells and IL-9. Therefore, more research particularly in human patients is required to provide sufficient data for drawing a concrete conclusion about the implication of Th9 and IL-9 in transplantation.

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: This work was supported by the Wellcome Trust (grant nos. 057704 and 085851/Z/08/Z). Part of this data was presented as a poster and the abstract published in the journal Immunology (2011;135:71).

: Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

^∗: These authors contributed equally to this work.

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Asthma and lower airway diseaseActivin A and TGF-β promote TH9 cell–mediated pulmonary allergic pathology

Background

Objective

Methods

Results

Conclusion

Section snippets

Mice

Induction and analysis of allergic airway inflammation

TH9 cells are generated in the lungs following exposure to allergen and are associated with atopy in patients

Discussion

Immunity

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Biol Chem

Interleukin 9: a candidate gene for asthma

Proc Natl Acad Sci U S A

Allelic association of gene markers on chromosomes 5q and 11q with atopy and bronchial hyperresponsiveness

Am J Respir Crit Care Med

Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes

J Immunol

IL-9 governs allergen-induced mast cell numbers in the lung and chronic remodeling of the airways

Am J Respir Crit Care Med

Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness

J Exp Med

Th9 and allergic disease

Immunology

IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(−) effector T cells

Nat Immunol

Transforming growth factor-beta “reprograms” the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset

Nat Immunol

The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation

Nat Immunol

Regulation of IL-9 expression by IL-25 signaling

Nat Immunol

Asthma and lower airway disease
Activin A and TGF-β promote T_H9 cell–mediated pulmonary allergic pathology

T_H9 cells are generated in the lungs following exposure to allergen and are associated with atopy in patients