What is already known on this topic
The alteration of the gut microbiota make-up has been linked to a series of immune disorders associated with impaired immunosuppressive function of Foxp3+ T regulatory (pTreg) cells. Previous studies have shown that commensal bacteria are involved in pTreg generation, but the underlying molecular mechanisms remain unknown.
What this research adds
Researchers have identified β-glucan/galactan polysaccharides derived from the cell wall of the probiotic Bifidobacterium bifidum (Bb) as promoters of pTreg cell induction in the gut. This process relies on gut-resident dendritic cells that express Toll-like receptor 2.
The study opens up the possibility of using microbial components such as cell surface β-glucan/galactan polysaccharides to treat disorders like colitis and food allergies.
A group of cell-wall sugar molecules called cell surface β-glucan/galactan polysaccharides (CSGGs) stimulate the production of Foxp3+ T regulatory (pTreg) cells, which reduce inflammation and prevent autoimmunity. That’s the conclusion of a study done in mice and led by Ravi Verma at the Institute for Basic Science in Pohang, Republic of Korea. The results are detailed in Science Immunology.
The gut microbiota has been implicated in several immune diseases, from autoimmunity to gastrointestinal inflammatory disorders. Gut bacteria are thought to modulate the host immune system by inducing the differentiation of specific immune cells, including Foxp3+ T regulatory (pTreg) cells, which have anti-inflammatory and immunosuppressive functions.
Several studies have shown the immunomodulatory effects of certain mucosa-associated bacterial species, but the molecular mechanisms that regulate these processes are unclear. To identify beneficial bacteria and assess the mechanisms underlying their activity, the researchers have screened a collection of probiotic strains for their ability to induce pTreg cells, and identified the gut commensal Bifidobacterium bifidum (Bb) as the best candidate.
Bb induces the differentiation of pTreg cells
Three weeks after administering Bb to germ-free mice, the researchers registered a substantial increase in the frequency of pTreg cells in the colon as well as in other organs, including the spleen and mesenteric lymph nodes. In particular:
- Treg cells in the colon of mice colonized with Bb showed a higher proportion of CD103+ cells compared with Treg cells in germ-free mice
- Treg cells induced by Bb colonization produced higher levels of immunosuppressive and anti-inflammatory molecules such as CTLA4 and IL-10
- Treg cells induced by Bb colonization exhibit low expression of Helios and NRP1, two markers associated with thymically derived, but not peripherally induced, Treg cells
Bb induces pTreg cells that recognize a broad range of antigens
Next, the team assessed the T cell receptor (TCR) specificity of Treg cells induced by Bb colonization. These cells showed a highly diverse TCR repertoire and recognize Bb as well as other antigens.
To further test the immunomodulatory capacity of Bb-induced Treg cells, the researchers used a mouse model of colitis, in which T cells are activated in response to bacterial flagellin. The results show that mice gavaged with Bb were protected from colitis, suggesting a key role of Bb in stimulating a “tolerant” gut environment.
Bb-derived CSGGs facilitate Treg cell induction
Having shown the beneficial effects of Bb, the researchers set to identify Bb-derived molecules that induce Treg cells. Subfractionation and nuclear magnetic resonance analysis of cell-wall sugar molecules revealed that cell surface β-glucan/galactan polysaccharides (CSGGs) are able to stimulate Treg cell differentiation in vitro.
Further experiments showed that CSGGs induce Treg cells through the generation of regulatory dendritic cells (DCs). Indeed, treatment of naïve CD4+ T cells with CSGGs in the presence of DCs induced Foxp3+ Treg in a dose-dependent manner, whereas the same treatment in the absence of DCs failed to do so. What’s more, CSGG treatment resulted in:
- Increased levels of anti-inflammatory cytokines IL-10 and TGF-β1
- Reduced levels of pro-inflammatory IFN-γ
- Altered gene expression of intestinal DCs through a Toll-like receptor 2-dependent mechanism
CSGG-induced Treg cells suppress gut inflammation
To test whether CSGGs alone could ameliorate progression of inflammatory colitis, the researchers transferred naïve CD4+ Foxp3− T cells into mice that lacked adaptive T and B cells. Then, they injected the animals with CSGGs. CSGG treatment suppressed colitis development, and was associated with an increased frequency of Treg cells as well as with a decrease in the frequency of IFN-γ-producing T cells.
In conclusion, the study shows that Bb-derived CSGGs can induce the differentiation of Foxp3+ Treg cells, alleviating gut inflammation in a mouse model of colitis. The finding opens up the possibility of using bacteria-derived components to increase protective immunity and limit inflammation. The authors speculate that CSGG-producing Bb could be considered as a treatment for allergic diseases.