Select microbiota species provides protection against food allergy via RORγt+ Tregs

It is now undoubtedly acknowledged that body's microbiota plays a decisive role in protection against allergy, including food allergy. But how exactly microbiota does it is less clear.

A new study in mice published in Nature Medicine suggests the certain microbiota species signal subset of FOXP3+ Tregs called RORγt+ Tregs via adaptor MyD88 to exert its protective role against food allergy.

The most of the experiments reported here were done in genetically modified mice called Il4ra^F709 that shows a predisposition to allergy due to an alteration in IL-4 signaling. Here, germ-free Il4ra^F709 mice were colonized with microbiota consortium differently enriched between non-allergic versus allergic infants. Out of those, defined mix of Clostridiales and Bacteriodales but not Proteobacteria could reduce allergic reaction in Il4ra^F709 mice. (Note, you can click the image to expand it to see it more accurately).

In a separate set of experiments the authors noticed that Il4ra^F709 mice or mice specifically deficient for RORγt+ Tregs subset displayed similar phenotype in response to allergic challenge. They thought there could be a connection.

Indeed, Il4ra^F709 mice deficient for RORγt+ Tregs subset lost an ability to resist allergic reaction when colonized with defined mix of Clostridiales and Bacteriodales.

Finally, the authors attributed the loss of protection to loss of MyD88 adaptor signaling in Tregs because Il4ra^F709 mice deficient for MyD88 signaling in Tregs also showed loss of protection against allergic reaction when colonized with defined mix of Clostridiales and Bacteriodales (Note, oral short chain fatty acid (SCFA) therapy failed to protect Il4ra^F709 mice against allergic response) .

In summary, we could conclude based on this and other studies that RORγt+ Tregs do play a decisive role in protection against unwanted inflammatory response (Note, however, that allergic sensitization protocol employed here is not exactly "translational" approach).

One major drawback of this study is that the authors failed to examine why it is that Clostridiales and Bacteriodales but not Proteobacteria or other species could signal via MyD88 to provide protection against allergic response. In my view it is not a difference in innate signaling molecules that distinguishes protective versus non-protective microbiota species but rather their antigenic composition that provides epitopes to RORγt+ Tregs to keep them active and in a good functioning condition (MyD88 could be just necessary to keep such antigen-specific Tregs active due to its role in metabolic pathways).

posted by David Usharauli

Monocyte hyperactivity at birth correlates with susceptibility to food allergy in infants

Every time I read a new article from Science Translational Medicine (STM) I have a distinct feeling that something is not right with its editorial board. For some reason, immunology papers published at STM usually start strong and clear and but end weak and confused, as if two different teams worked on them.

For example, this week STM published a very interesting study about immune correlates of food allergy in infants. Journal Science itself had a news/views story about it on its website.

Now, I did analysis of this study for my immunology blog. So I wanted to share my reading experience of this paper.

Basically, for this study the authors had first collected cord blood cells from large cohort of newborn babies. Then, they have conducted surface phenotype and functional assays on those cord blood cells. In parallel, they have followed up with those babies up to 1 year to see who would show any susceptibility to allergens in skin prick test (SPT).       

In Figure 1, the authors showed that compared to non-allergic infants, monocytes from newborns who later developed allergies showed hyperactivity (IL-6↑, TNF-α↑, IL-1β↑) when stimulated in vitro with 1 µg/ml LPS (this dose of LPS is quite high. However they did not show dose titration results to see if this difference is apparent at high LPS dose only).

In the same Figure 1, the authors also showed that cord blood of infants who later developed food allergies had high ratio of monocytes to CD4 T cells (CD14⁺monocyte / CD4⁺ T cell ratio). Its all.

Afterwards, in Fig 2 and 3, the authors went on to show how exogenous cytokines influenced "generic, pooled" cord blood-derived CD4⁺ T cell differentiation. However, they did not compare CD4⁺ T cells derived from allergic-prone and non-allergic infants. So, basically these Fig 2 and 3 are completely uninformative.

In summary, this study analysed cord blood samples from 697 newborn babies and found that presence of large number of hyperactive monocytes in newborn babies correlated with food allergy development by age 1.

So what could we conclude from study that analysed cord blood samples from so large newborn cohort and found only 1 non-specific correlate to food allergy? And what presence of hyperactive monocytes really means? I would expected that STM would demand more vigorous quality.

David Usharauli