Thursday, October 12, 2017

Microbiota-generated butyrate works on Aire to amplify Treg numbers

A short but very interesting paper in Journal of Immunology caught my attention this week. In this study the scientists showed that butyrate, a short chain fatty acid derived from fiber fermentation by microbiota acts on GPR41 receptor in the thymus to increase Aire expression and amplify Foxp3+ Treg frequency (of note, compared to WT, GPR41-KO thymus already contains almost 5-fold less Tregs).  

Generally it is believed that microbiota works locally in the gut or other peripheral tissues to either convert naive T cells into Foxp3+ Tregs or expand existing Treg numbers. However no one yet managed to definitely show which pathway is functionally operational in vivo in physiological conditions. This study now could help to further narrow down biological mechanisms responsible for Treg biology. If microbiota-generated butyrate could work on thymus to increase Aire expression that in turn increases level of Thymus-derived Treg generation, then peripheral conversion pathway may play even less relevant role in physiological mechanisms of tolerance.  

The most obvious question after reading this article is why the authors did not test Aire KO mice to verify their conclusions.

posted by David Usharauli


Friday, September 29, 2017

Gut IgA are naturally microbiota-reactive and polyreactive (cross-reactive)

Gut immune system naturally produces large quantities of IgA, an antibody isotype frequently found at mucosal surfaces. Since these IgA antibodies are found in mice in absence of immunization and infection they were dubbed natural and were thought to be specific for microbiota or food antigens. However a formal proof for such conclusions were lacking. 

This week journal Science published a new study from Bendelac's Lab to show that these naturally occurring IgA antibodies are present even in mice devoid of microbiota or food antigens.

In this study the authors analyzed specificity of IgA antibodies using single cell analysis. Interestingly, IgA bound to some but not to all microbiota species. 

Furthermore, most of gut IgA bound to all kind of microbiota-derived components showing a broad polyreactivity (cross-reactivity). Separate test using broadly-neutralizing antibody (bnAb) panel directed against influenza stalk region showed co-staining for microbiota coated by IgA. 

Interestingly, unlike other tissues, numbers of IgA+ plasma cells in small intestine were not reduced in germ-free mice.

Even more surprising, numbers of IgA+ plasma cells in small intestine were not reduced in germ-free mice fed antigen-free diet (amino acid diet).

These results suggest that 

(a) not all microbiota species are targeted by IgA that by itself requires further studies to understand why it is the case.

(b) natural, microbiota-reactive IgA in small intestine develop in absence of exogenous antigenic stimulation that suggests that such specificities are inherited and accumulate spontaneously. 

(c) selection of broadly neutralizing antibodies against viruses could be influenced by microbiota-derived antigens (polyreativity, cross-reactivity)  

posted by David Usharauli

Saturday, September 16, 2017

Tolerance to insulin is maintained by Foxp3+ Tregs

A new study in Journal of Immunology suggests that tolerance to insulin is maintained by Foxp3+ Tregs rather than by deletion of insulin-reactive T cell clones. 
Here, the authors reconstituted mice with T cells on scid background transduced either with high (4-8) or low (12-4.1) affinity TCR specific for native insulin peptide (insulin epitope B:9–23). In addition, each of TCR construct were fused with either native insulin (INS) or modified insulin carrying super-affinity peptide (R22E). All mice expressing either INS or R22E but not irrelevant HEL were protected from developing diabetes.

The authors showed that while R22E deleted developing insulin-specific T cell clones in the thymus, native INS did not.

In fact, the authors showed that if the T cells also lacked Foxp3 molecule (scid-scurfy), then protection against diabetes was lost in mice exposed to native INS.

This study could be interpreted to show that with the exception of  epitopes which are able to delete (purge) cognate T cell clones in the thymus, tolerance to self in the periphery is maintained by thymic-derived Foxp3+ Tregs.

posted by David Usharauli