T_reg induction by a rationally selected mixture of Clostridia strains from the human microbiota

Koji Atarashi, Takeshi Tanoue, Kenshiro Oshima, Wataru Suda, Yuji Nagano, et al.
Nature 2013 August; 500: 232–236.

Speaker: Yi-Wen Liu (劉怡彣)                                     Time: 13:00~14:00, Jan. 08, 2014

Commentator: Dr. Jenn-Wei Chen (陳振暐 老師)      Place: Room 601

Abstract

CD4⁺ regulatory T cells (T_regs), which express the Foxp3 transcription factor, play a critical role in the maintenance of immune homeostasis.¹ Previous study demonstrated that the intestinalmicrobiota, particularly clusters IV and XIVa of the genus Clostridium, promoted T_reg cells accumulation.^{2, 3} In this study, the authors selected 17 strains within Clostridia clusters IV, XIVa and XVIII from healthy human faecal sample with pronounced number of T_reg cells in the colon. The 17 strains all have high potency in inducing interleukin-10 (IL-10) and inducible T-cell co-stimulator (ICOS) in germ-free mice. IL-10⁺ T_reg cells can express high levels of CTLA4, which are essential for the immunosuppressive activity of T_reg cells; and ICOS is required for the T_reg-mediated suppression of T_H2 responses. Furthermore, the community of 17 strains incubated with various human and mouse intestinal epithelial cell lines provided an environment rich in transforming growth factor-β (TGF-β), but not IL-6 and TNF-γ. TGF-β is a key cytokine for differentiation and accumulation of T_reg cells, and affects the function and number of Foxp3⁺ T_regs in the colon. The authors also examined T_reg cells induction by randomly selected combinations of 3-5 strains from the 17 strains. Although all tested combinations of 5-mix induced T_reg cells, the magnitude was substantially lower than that observed in 17-mix mice. It seems likely the 17 strains act synergistically to amplify the induction of T_reg cells in a microbial-community-dependent fashion. Therefore, the authors postulated that a collection of functionally distinct bacterial species rationally selected from the human gut microbiota may be more effective than single strains. The outcome may suggest that supplementation with the 17-strain bacterial community might counterbalance dysbiosis, induce T_reg cells and aid in the management of allergic and inflammatory conditions.

References

1. Round, J. L. & Mazmanian, S. K. (2010) Inducible Foxp3⁺ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107: 12204-12209.
2. Geuking, M. B. et al. (2011) Intestinal bacterial colonization inducesmutualistic regulatory T cell responses. Immunity 34: 794-806.
3. Atarashi, K. et al. (2011) Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331: 337-341.