Foxp3+ T regulatory cells (Tregs) are thought to regulate immune system. But who regulates the regulators? Any biologically functioning regulatory network should be based on feedback mechanism. If tissue regulates Foxp3+ Tregs, then Foxp3+ Tregs should be able to sense the state of the tissue and vice versa.
Alternatively, a gut microbial flora is a good candidate for regulation of Tregs. Based on what we have already uncovered about gut microbiota, I expect that many of our physiological functions will be found to be fine tuned by gut flora (food taste, mating preferences or even aging).
This new paper (1) I am going to review this time was published in Immunity (lots of good papers started to appear in Immunity indicating better editorial control on quality) and came from Sidonia Fagarasan's lab in Japan. She is one of the most interesting and fascinating scientists. Originally from Romania, she made her famed career as immunologist in Japan, quite an extraordinary achievement for a female scientist to do it in that male-dominated scientific circle.
Her lab's main focus is IgA production and its regulation. In recent years, her lab published several papers linking Foxp3+ Tregs with gut IgA production and role of gut flora in all this.
This new paper is a further refinement in that direction. I liked it because it has one very cool and visually effective figure (see big figure below) that simplifies understanding of the complex data about gut microbiome.
IgA is a signature Immunoglobulin of mucosal surfaces. Mucosal surfaces are the critical spaces where our immune system comes in contact with microbes and has to decide what to do.
First, this paper has compared the gut microbiome composition of mice that lack T cells (CD3e -/-) or B cells (Ighm-/-) or both (RAG1 -/-). In all these cases, gut microbiome diversity and phylogenetic structure were affected by the absence of either T or B cells. The authors speculated that it has to do with lack of IgA and/or Foxp3+ T reg production.
To directly examine this hypothesis, the authors used adoptive transfer experiments. Specifically, they transferred naïve T cells or Tregs, separately or together into T cell-deficient CD3e-/- mice. Unlike naïve T cell transfer (that caused colitis), transfer of Tregs alone or with naïve T cells restored microbiome diversity and its phylogenetic structure of recipient CD3e-/- mice to the level seen in wild-type mice (though they don't show wt mice gut flora in this particular graph ). Especially striking effect were seen with bacteria called Firmicutes cluster IV and XIVa and XVIII. These results indicated that not only gut bacteria can influence T reg induction (as previously reported), but Tregs in turn can influence the composition of gut flora.
Interestingly, transfer of Foxp3+ Tregs into T and IgA double deficient mice failed to restore microbiome diversity and its phylogenetic structure, implying that local production of IgA was necessary to mediate Tregs effect on gut flora.
In addition, co-transfer of naïve T cells with Tregs that lacked bcl6 expression (necessary for GC follicular Treg development) also failed to restore gut Firmicutes, while still capable of preventing colitis. This showed that GC function of transferred Tregs was important for gut flora normalization.
Next, the authors tested the effect of Foxp3+ Treg-educated gut flora on naïve germ-free (GF) mice. As expected, transfer of Treg-educated gut flora (basically, feces) from donor CD3-/- mice into recipient ex-GF mice promoted IgM to IgA switch, while naïve T cell-educated gut flora induced IgG1 switch as well. Alternatively, when CD3-/- GF mice initially received Treg- or naïve T cell-educated gut flora and then received Treg cells, T reg-educated gut flora promoted donor Treg expansion, GC and IgA generation, while naïve T cell-educated gut flora lacked this properties. These results showed that T reg-educated gut flora acted as a messenger for further amplification or maintenance of Foxp3+ Treg population.
It would have been interesting to see whether T reg-educated gut flora could suppress colitis induction in CD3-/- ex-GF recipient mice when transferred with donor naïve T cells.
In summary, the data from this paper suggest that Foxp3+ Tregs modify and educate gut flora composition through IgA production, which in turn can amplify gut associated T reg-IgA axis.