Unravelling the role of TGFβ in allergic immune responses

February 11, 2016

 

The challenges faced by the mucosal sites of the airways are complex and continuous. Exposed to billions of potential threats each day, the pulmonary immune system must not only be primed to respond to inhaled pathogens from the airways, it must also be capable of quickly distinguishing between harmful threats and harmless particles. An immune response to a virus would be beneficial, for instance, whereas a response to something as innate as dust or pollen would be unnecessary and potentially damaging to the host. If threats are to be quickly and correctly recognised, the innate immune system must be carefully regulated and sustained.

 

As the most superficial surface of the airway mucosa, the epithelium plays a vital role in this recognition process by dictating how the immune system will interpret the threat of inhaled particles, and the response it will subsequently induce. The epithelium achieves this control by releasing explicit profiles of chemokines and cytokines to recruit and activate specific immune cells. Since each group of immune cells specialises in different aspects of host defence, the epithelium must choose particular cells to generate the immune response it needs. Correspondingly, if the epithelium mistakes a harmless particle for a threat and then selects a set of immune cells to eliminate the threat, the immune response mounted will be potentially detrimental. In a study published in Immunity in November last year, Laura Denney, Clare Lloyd and colleagues from Imperial College London have described one of the ways in which the epithelium fulfils this role. Using mouse models of allergy, Denney and Lloyd have shown that one cytokine in particular, TGFβ, is released from the epithelium to attract a specific group of immune cells known as type 2 innate lymphoid cells (ILC2s) to the airway mucosa, where they initiate an early allergic immune response.

 

TGFβ is a well-studied cytokine produced by various leukocytes but also by structural cells within the airways, including epithelial cells. In human cells and animal models TGFβ is already known to drive pathological processes such as fibrosis,[1-4] and polymorphisms in its gene have been linked to asthma susceptibility.[5,6] Importantly, however, the effects of TGFβ are not entirely undesirable; a notion indicated by the fact that multi-organ inflammation and early death occur if TGFβ is completely removed from the body.[7-8] If TGF-β is necessary for life, but also has the capacity to trigger unwanted pathological effects, it is possible that an imbalance of TGFβ – if it was incorrectly produced by the airway epithelium, for instance – could play a part in disease.  

 

By using a Cre recombinase system to selectively eliminate TGFβ from the airway epithelium in mice, and then exposing the mice to an allergen (in this case, house dust mite protein), Denney and Lloyd examined whether TGFβ from the airway epithelium was needed to mount an allergic immune response against the allergen – a process significant in allergic asthma. Without epithelial-derived TGF-β, airway hyperresponsiveness and airflow resistance (both hallmark features of asthma) triggered by the allergen were weaker, and less IL-4 and IL-13 were produced, two cytokines with prominent roles in asthmatic inflammation. In these mice the allergen also failed to produce as many eosinophil chemokines and growth factors, and fewer eosinophils were recruited to the lungs.  These results led to the conclusion that TGFβ production by the airway epithelium was necessary for an allergen to induce asthma-like features in mice.

 

Given the conspicuous role of IL-13 in certain features of asthma, such as mucus overproduction and bronchoconstriction, the smaller quantities of IL-13 produced by mice lacking epithelial TGFβ was particularly interesting. To understand why this had occurred Denney and Lloyd examined the prevalence of possible cellular sources of IL-13, and found fewer ILC2s in the airways of mice when epithelial TGFβ was absent, even though other sources such as T helper 2 cells were still present as expected after an allergen challenge. This implied that TGFβ production by the airway epithelium was necessary for ILC2 accumulation in the lungs, and therefore might explain how and why allergic asthmatic responses were weakened in mice without TGFβ in the airway epithelium. 

 

To establish precisely how epithelial-derived TGFβ could affect ILC2 accumulation, Denney and Lloyd asked whether TGFβ interacted with IL-33, a cytokine known to drive ILC2 growth. When normal mice expressing epithelial TGFβ were treated with IL-33, this triggered a release of TGFβ specifically from the epithelium, rather than from other sources of TGFβ. Interestingly, the ILC2s were already prepared to respond to this TGFβ because they expressed the TGFβ receptor. But, in mice lacking epithelial-derived TGFβ, IL-33 failed to recruit as many ILC2s to the airway lumen, even though ILC2s were readily available in the lungs, and the resulting inflammation was weaker. The importance of TGFβ in this scenario was confirmed by administering a supplement of TGFβ to replace that missing in the airway epithelium. This restored inflammation and even increased ILC2 numbers. Investigating this further, Denney and Lloyd discovered that rather than acting as a chemoattractant for ILC2s, TGFβ “primed” the ILC2s, causing them to become increasingly responsive to chemotactic stimulation. In experiments, TGFβ enhanced IL-33-triggered accumulation of ILC2s by increasing the distance and speed at which the cells travelled. By working alongside IL-33 to promote ILC2 accumulation, TGFβ produced by the airway epithelium appeared to drive the inflammatory response to allergens. And, since the cells recruited were IL-13+ ILC2s, epithelial-derived TGF-β seemed to play a significant part in IL-13-driven allergic pathophysiology.

 

The findings of this study demonstrate the crucial ability of TGFβ to regulate immune responses, particularly in the airway epithelium, which, faced by endless environmental threats, must differentiate carefully between threats and harmless particles to avoid an unnecessary reaction. By producing this pivotal cytokine and thereby instructing immune cells, stromal cells such as airway epithelial cells evidently define how the host’s immune response will respond to the pathogens and potential allergens in its environment.

 

Image source: Annie Cavanagh, Wellcome Images

 

References:

  1. Roach KM, Feghali-Bostwick C, Wulff H, Amrani Y, Bradding P. Human lung myofibroblast TGFβ1-dependent Smad2/3 signalling is Ca(2+)-dependent and regulated by KCa3.1 K(+) channels. Fibrogenesis Tissue Repair 2015; 8: 5

  2. Hackett TL, Warner SM, Stefanowicz D, Shaheen F, Pechkovsky DV, Murray LA, Argentieri R, Kicic A, Stick SM, Bai TR, Knight DA. Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-beta1. Am J Respir Crit Care Med 2009; 180(2): 122-33

  3. Gregory LG, Mathie SA, Walker SA, Pegorier S, Jones CP, Lloyd CM. Overexpression of Smad2 drives house dust mite-mediated airway remodelling and airway hyperresponsiveness via activin and IL-25. Am J Respir Crit Care Med 2010; 182(2): 143-54

  4. Kariyawasam HH, Pegorier S, Barkans J, Xanthou G, Aizen M, Ying S, Kay AB, Lloyd CM, Robinson DS. Activin and transforming growth factor-beta signaling pathways are activated after allergen challenge in mild asthma. J Allergy Clin Immunol 2009; 124: 454–462

  5. Li H, Romieu I, Wu H, Sienra-Monge JJ, Ramírez-Aguilar M, del Río-Navarro BE, del Lara-Sánchez IC, Kistner EO, Gjessing HK, London SJ. Genetic polymorphisms in transforming growth factor beta-1 (TGFB1) and childhood asthma and atopy. Hum Genet 2007; 121: 529–538

  6. Silverman ES, Palmer LJ, Subramaniam V, Hallock A, Mathew S, Vallone J, Faffe DS, Shikanai T, Raby BA, Weiss ST, Shore SA. Transforming growth factor-beta1 promoter polymorphism C-509T is associated with asthma. Am J Respir Crit Care Med 2004; 169: 214–219

  7. Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, et al. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 1992; 359: 693–699Barlow JL, Peel S, Fox J, Panova V, Hardman CS, Camelo A, Bucks C, Wu X, Kane CM, Neill DR, et al. IL-33 is more potent than IL-25 in provoking IL-13-producing nuocytes (type 2 innate lymphoid cells) and airway contraction. J Allergy Clin Immunol 2013; 132: 933–941

  8. Li MO, Flavell RA. TGF-beta: a master of all T cell trades. Cell 2008; 134: 392-404

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