It is well recognized that the function of the intestinal immune system depends on the fine balance between effector, tolerogenic, and regulatory mechanisms. This balance is important not only in preventing disease, but also in providing flexibility and thus instructing the appropriate immune response. Dysregulation in any components of this homeostasis has been known to contribute to IBD. Intestinal commensal bacteria are known to affect multiple immune mechanisms and mouse models of IBD depend on the presence of microbiota. However, the role of the composition of the microbiota ihas not been investigated and whether different taxons of commensal bacteria activate specific branches of the immune system is not known. Th17 cells are a newly discovered helper T cell population that has been proposed to play pro-inflammatory role in the context of IBD. At steady state Th17 cells are exclusively present in the small intestinal lamina propria where they co-exist in a well-regulated balance with Foxp3+ regulatory T cells (Treg). The role of different components of the intestinal microbiota in regulating this balance is currently unknown. We have discovered that the Th17:Treg ratio depends on the composition of the intestinal microbiota. The focus of the current proposal will be to further investigate the role of gut bacteria in this process. Our main hypothesis is that specific components of the commensal intestinal microbiota can be identified to specifically induce Th17 cells with protective function in the intestine. To test this hypothesis, we propose to 1) identify bacterial taxons that specifically induce Th17 cell differentiation;2) examine the mechanisms of their action in vivo and 3) test their involvement in both mucosal and systemic immunity. We will perform most of the experiments in 1) during the K99 phase and the bulk of the experiments in 2) and 3) in the independent phase of the award. Information gathered from these studies will provide major advances in our understanding of the regulation of intestinal immune responses by commensal bacteria. The ultimate goal will be to provide knowledge for the rational design of therapeutic strategies for IBD, based on modulations of the composition or function of the intestinal microbiota.
We propose the attractive idea that the nature of the immune responses in the gut during both steady state and disease is controlled by the composition of the intestinal microbiota. Identification of Th17 or Treg cell-inducing taxons of bacteria and their mechanism of action will allow for the design of novel therapeutic strategies for IBD or intestinal infections by modulating the immune response through regulating the composition of gut bacteria or their function.
|Kunisawa, Jun; Gohda, Masashi; Hashimoto, Eri et al. (2013) Microbe-dependent CD11b+ IgA+ plasma cells mediate robust early-phase intestinal IgA responses in mice. Nat Commun 4:1772|
|Goto, Yoshiyuki; Ivanov, Ivaylo I (2013) Intestinal epithelial cells as mediators of the commensal-host immune crosstalk. Immunol Cell Biol 91:204-14|
|Ivanov, Ivaylo I; Honda, Kenya (2012) Intestinal commensal microbes as immune modulators. Cell Host Microbe 12:496-508|
|Sczesnak, Andrew; Segata, Nicola; Qin, Xiang et al. (2011) The genome of th17 cell-inducing segmented filamentous bacteria reveals extensive auxotrophy and adaptations to the intestinal environment. Cell Host Microbe 10:260-72|
|Lewis, Kanako L; Caton, Michele L; Bogunovic, Milena et al. (2011) Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity 35:780-91|
|Atarashi, Koji; Tanoue, Takeshi; Shima, Tatsuichiro et al. (2011) Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331:337-41|