Wednesday, April 15, 2020

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