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

Antigen-specificity of human FOXP3+ Tregs

Foxp3+ regulatory T cells (Tregs) control immune response to prevent immunopathology. However, unlike conventional T cells, it is hard to determine antigen-specificity of Foxp3+ Tregs in a random T cell pool. Tregs do not secrete anything unique and they do not even proliferate when exposed to antigens in vitro, two functional readouts that are still used as a gold standard for determining antigen-specificity of conventional T cells. 

Hence, we have no clue as to antigen[epitope] specificity of vast majority of human Tregs. Specificity of T cells could be also determined by non-functional readout such as tetramer staining. This is what the authors in new PNAS paper have used to determine antigen-specificity of Tregs. 

They found that adult human peripheral blood contains FOXP3+ T cells that stain with tetramers specific for self as well as nonself peptides (Flu, melanoma protein, HIV epitopes).

Interestingly, frequency of antigen[epitope]-specific FOXP3+ Tregs varied among donors, but they were, on average, equally distributed among self and nonself [epitope]-specific Tregs, except Flu HA epitope.  

Finally, comparison of neonatal [cord blood] and adult blood revealed that actual number of [epitope]-specific Tregs / per ml of blood did not change much between newborn and adult indicating that most of Tregs tested in this study were generated already by the time of birth.

In summary, this study revealed that human peripheral blood contain Tregs specific for both self nonself antigens. Since tested donors were negative for some of the infection such as HSV, CMV or HIV, it begs the question what [cross-reactive?] antigens maintain CMV or HIV-specific Tregs in antigen-naive [antigen-unexposed] hosts?    

David Usharauli