Do Tregs inhibit or promote allergic responses? How to avoid data misinterpretation

Foxp3+ regulatory T cells (Tregs) are the most essential component of the immune system. No other cell population, taken singularly, have such an indispensable role in the proper functioning of the immune system. Tregs are known to inhibit inappropriate immune response against self-antigens, commensal microbiota or even nonself pathogens.  I strongly believe that data are very clear about it.

So, when I see a well-designed research paper showing something contrary I immediately want to understand its details. Take this new paper from The Journal of Clinical Investigation (JCI) as an example. It claims and data its provided is pretty solid that removal of a subset of Tregs called T follicular regulatory cells (Tfr) from the immune system in Foxp3-cre Bcl6-fl/fl mice paradoxically reduces, rather than increases, peanut-specific IgE responses. 

And if you think maybe their knockout mice are some kind of weirdos, not really. Their model also shows that total IgE is increasing as expected. So, the system the authors are using is within acceptable norms.   

The authors then went on to show that IL-10 derived from Tfr cells are important for promoting peanut allergy-producing IgE production. 

These results are totally against the whole paradigm about the role of Tfr cells and even IL-10 because the authors speculating that we need to block IL-10 to reduce peanut allergy rather than inject IL-10 to inhibit it, as everyone thinks currently (IL-10 is lesser understood cytokine but it is generally accepted as an immunosuppressant.)

So, how to interpret these results? Basically, what's going on? Is there a way to interpret these results within the confines of the established concept?

I think there is at least one possibility the authors did not consider in their discussions. Here the authors are looking for primary adaptive T/B cell response to a novel antigen, peanut antigen in this case. In this scenario, peanut allergy promoting IgE response is clearly reduced without Tfr cells. But at the same time, the level of total IgE (representing unknown antigen-specific IgE responses) has increased. We could say that total IgE is derived from an already established memory T/B system rather than from primary immune response as peanut IgE is. This memory T/B/plasma cells then boost total IgE levels when the brakes applied by Tfrs are removed. But the same principle does not apply for primary T/B response to peanut allergen. Why is that? It is possible that the absence of Tfr specifically messes up with primary T/B cooperation. It is not a direct effect but rather indirect due to the activation of other components of the immune system when brakes are removed. So, primary T/B responses will be undermined by a lack of Tfr cells and it would appear if Tfr cells were promoting primary IgE responses and their absence reduced IgE production. 

The correct interpretation is essential, especially when applied to human clinical data. In humans, peanut allergy IgE is already established as a memory system by the time the allergic individuals are examined by a doctor. In that case, manipulation of the Tfr or IL-10 system the way the authors envisaged could be detrimental rather than beneficial.     

posted by David Usharauli      

IL-33 → MyD88 pathway drives type II immunity in female genital mucosa

Type II immunity underlies several types of immune conditions such as asthma, allergy or response to parasitic helminths. It is not yet fully clear how type II immunity contributes to host's defenses. At this stage scientific inquiry is mostly focused on uncovering cellular and molecular mechanism behind type II immunity.

For example, PNAS has published new paper supporting role of locally produced IL-33 in promoting type II immunity.

For these experiments the authors have used papain, a well established experimental type II inducer protease. As reported before, papain required enzymatic activity for its type II response.

Papain application to female vaginal mucosa induced IL-33, a member of IL-1 family implicated in type II immunity.

Indeed, IL-33 deficient mice showed reduced secretion of components of type II immunity (IL-4, IgE).

Interestingly, type II immunity in response to papain in female genital tract depended on IRF4⁺ CD11c⁺ dendritic cells but it was independent of basophils and eosinophils.

Furthermore, type II immunity in response to papain application to female vaginal tissue depended on MyD88 signaling.  

In summary, this study confirms the role of IL-33 in type II immunity.

David Usharauli

Wiskott-Aldrich syndrome protein (WASp) deficient FOXP3+ Tregs fail to control IgE mediated allergies

The inherited immunodeficiencies are frequently characterized with dysregulated Th2 responses, atopy, and elevated IgE levels. Mutations in Foxp3, STAT3, DOCK8, PGM3, LAT, ZAP70, or RAG result in hyper IgE phenotypes. Mechanism is unclear.

This time the scientists found that patients with another inherited immunodeficiency disorder, called Wiskott-Aldrich syndrome (WAS), also show elevated IgE signature and increased frequency of sensitization to food allergens. In mouse model, selective deficiency of WAS protein in FOXP3+ Tregs could recapitulate hyper IgE signature.

For this study the researchers analyzed "the overall burden of clinical food allergy within a cohort of 25 patients with mutations in the WAS gene" and found that individuals with WAS mutations were more likely to demonstrate serum sensitization to peanut, milk, and egg (compared to the general population).

Lab mice deficient for WASp also display elevated IgE (and IgG1) antibody levels to components of their chow food (even on germ-free background).

Since WASp is expressed in different cell types, the authors tested mice selectively deficient for WASp in B cells, DCs or FOXP3+ Tregs. Out of these gene-modified mice, only Was^fl/fl Foxp3-Cre mice showed deviation to Th2 phenotype and development of IgE to chow food.

In vitro T cell stimulation confirmed that total T cells from Was^fl/fl Foxp3-Cre mice showed selective enhancement in Th2 cytokines.

In sum, these results indicate that mice with selective deficiency of WASp in FOXP3+ Tregs display excess in Th2 subsets. It is possible that absence of WASp destabilizes FOXP3+ Tregs and this somehow drives their de-differentiation into Th2-like cells (and not into Th1 or Th17, for instance).

David Usharauli