Preprint Club
A cross-institutional Journal Club Initiative

Keywords

• eosinophilic allergic airway inflammation

• neutrophilic allergic airway inflammation

• Tregs

Main Findings

Allergic airway inflammation, a chronic immune response to environmental antigens, involves diverse immune cell types, with main drivers of traditional allergic reactions being CD4+ T helper 2 (Th2) cells and eosinophils. On the other hand, steroid resistant severe asthma patients tend to have neutrophilic and eosinophilic mixed airway inflammation. Another important cell type in allergy is the Foxp3+ regulatory T cells (Tregs), which are essential for the regulation of inflammatory processes and their disruption can lead to excessive inflammation. As such, Tregs present in inflamed tissues can adapt varied phenotypes, influenced by specific tissue sites, and can exhibit substantial heterogeneity and tissue residency. Understanding this cell diversity of the disease better can thus lead to differential therapy options.

The preprint by Iamsawat et al. used single-cell RNA sequencing (scRNAseq) to investigate the diversity of lung-infiltrating Tregs in models of eosinophilic and neutrophilic airway inflammation models. They found that lung infiltrating Tregs are highly heterogeneous and that non-circulating CD103+ Tregs displaying lung resident phenotypes are significantly different depending on the types of inflammation. Expression of ST2, a receptor for alarmin cytokine IL-33, was predominantly induced on tissue-resident Tregs during eosinophilic inflammation. However, Treg-specific ST2 deficiency did not affect the development of eosinophilic allergic inflammation nor the generation of lung resident Tregs, suggesting that ST2-mediated signalling on Treg may be dispensable for in these airway inflammation models.

The results highlight that different inflammatory settings give rise to phenotypically distinct lung resident Tregs, which indicates a novel mechanism by which inflammatory cues may shape the composition of infiltrating Tregs. The question arises if and how Tregs could be regulating inflammatory responses through tissue-adapted mechanisms.

Limitations

• Mouse models of allergy are never perfectly representative of human disease, especially when external adjuvants are added to induce disease. In this preprint, the use of two different types of adjuvants is understandably needed to induce different disease phenotypes. However, adjuvants may play a role in the differential gene expressions of Tregs and may be playing a role in creating the heterogeneity observed in this preprint. The preprint would benefit from investigating the Tregs in an adjuvant free mouse model or in naïve animals.

• The article is very explorative and descriptive which makes it very interesting for the researchers in the field and it opens up new questions for potential future research. However, due to the descriptive nature of the preprint, the authors, unfortunately, can only reach vague conclusions, which should be clarified better in their language in the text and can be further expanded on in the discussion pointing towards future research.

• The nature of the experimental design leads to the repetition of previously known facts in the field. While it is good to verify and validate previously known data, the preprint would benefit from delving into for example the mechanism with which Tregs develop residency and the function and the role of these cells upon repeated challenge.

• The authors state that ST2 is a unique Treg marker associated with alum-induced airway inflammation. While their data points for ST2 expression on Treg during alum-induced inflammation, ST2 is also expressed on for lung tissue resident memory CD4+ T cells. This makes ST2 not an optimal suggestion as a unique marker for lung Tregs but may be considered in addition to other markers.

• Moreover, the authors should consider assessing the role of ST2+ Tregs in the context of Alum-induced airway inflammation in light that a similar population has already been identified in the adipose tissue with known functions (PMID: 25599561).

Significance/Novelty

This preprint showed for the first time the heterogeneity of Tregs in different types of allergic inflammation and explored the discussed role of IL-33 signalling in modulating tissue residency of Tregs in the lung as well as in modulating inflammatory T cell responses.

Severe steroid resistant allergic asthma tends to show a neutrophilic phenotype and so understanding the differences of this phenotype and its pathophysiology can be crucial to developing better therapies for disease in the future. In this preprint, the authors take a step forward from in understanding Tregs in neutrophilic inflammation and opens new questions to be answered by the field.

Credit

Reviewed by Ece Danisman and Mariia Saliutina as part of a cross-institutional journal club between the Vanderbilt University Medical Center (VUMC), Charité – Universitätsmedizin Berlin, the Medical University of Vienna and other life science institutes in Vienna.

The authors declare no conflict of interests in relation to their involvement in the review.