Final Report Summary - DENDROWORLD (Mucosal dendritic cells in intestinal homeostasis and bacteria-related diseases.)
The gut is inhabited by trillions of microorganisms (recently called the microbiota) that are required for the correct functionality of the gut, including the digestive function and the development of immunity to pathogens accidentally ingested with the diet. Hence the microbiota has to be tolerated in the gut so to avoid unwanted immune inflammatory reactions, and to preserve intestinal homeostasis.
In this project we found that intestinal homeostasis is a very complex event comprising several cell-to-cell interactions including immune and non-immune cells. We found that murine dendritic cells that are pivotal in the induction of immunity and tolerance, release a cytokine called TSLP that is important to control the development of T regulatory (Treg) cells and T helper (Th)17 cells. Treg cells are involved in inhibiting the development of inflammation, while Th17 seems to be required for the initial phases of inflammatory bowel disease. The finding that TSLP released by dendritic cells can drive Tregs and limit Th17 development indicates an important role of this protein in the control of intestinal homeostasis. Indeed, in two mouse models of experimental colitis we demonstrate a function of this protein in protecting mice against colitis. We already demonstrated a function of TSLP released by epithelial cells in intestinal homeostasis in the human system but are further analyzing the role of TSLP produced by dendritic cells. We have analyzed the role of different subsets of dendritic cells in the induction of a mucosal antibody response to pathogens and to the microbiota. Indeed, bacteria induce in the gut the production of immunoglobulins of the IgA type. These antibodies are released in the intestinal lumen and are important for excluding bacteria from entering across the intestinal epithelium. IgA can also serve as an anchor for the microbiota to attach to the mucus and avoid to be washed out by the fecal stream. We have characterized a population of dendritic cells that is responsible for inducing a mucosal IgA response but we also observed that the way of induction of IgA responses to pathogenic versus non-pathogenic bacteria differs and is responsible most likely to control the type of microbiota of one individual over time. We also studied the role of bacteria in intestinal tumor development and have identified a signature of tumor-associated microbiota. We found that even before tumors are established there is a shift in microbiota composition. This may be relevant for diagnostic purposes.
In conclusions, in this project we have analyzed how the gut even if continuously exposed to external challenges preserves its integrity and is capable to quickly respond to changes. We found that the control of the well being of the gut derives from complex interactions between immune and non immune cells. We have identified some of the molecular players involved and that may be the target of future intervention in inflammatory bowel diseases. We also found that while the intestinal flora is in general beneficial to the host under certain circumstances it can contribute to promote disease like in intestinal cancers. Together, these finding open new avenues of intervention and prevention.
In this project we found that intestinal homeostasis is a very complex event comprising several cell-to-cell interactions including immune and non-immune cells. We found that murine dendritic cells that are pivotal in the induction of immunity and tolerance, release a cytokine called TSLP that is important to control the development of T regulatory (Treg) cells and T helper (Th)17 cells. Treg cells are involved in inhibiting the development of inflammation, while Th17 seems to be required for the initial phases of inflammatory bowel disease. The finding that TSLP released by dendritic cells can drive Tregs and limit Th17 development indicates an important role of this protein in the control of intestinal homeostasis. Indeed, in two mouse models of experimental colitis we demonstrate a function of this protein in protecting mice against colitis. We already demonstrated a function of TSLP released by epithelial cells in intestinal homeostasis in the human system but are further analyzing the role of TSLP produced by dendritic cells. We have analyzed the role of different subsets of dendritic cells in the induction of a mucosal antibody response to pathogens and to the microbiota. Indeed, bacteria induce in the gut the production of immunoglobulins of the IgA type. These antibodies are released in the intestinal lumen and are important for excluding bacteria from entering across the intestinal epithelium. IgA can also serve as an anchor for the microbiota to attach to the mucus and avoid to be washed out by the fecal stream. We have characterized a population of dendritic cells that is responsible for inducing a mucosal IgA response but we also observed that the way of induction of IgA responses to pathogenic versus non-pathogenic bacteria differs and is responsible most likely to control the type of microbiota of one individual over time. We also studied the role of bacteria in intestinal tumor development and have identified a signature of tumor-associated microbiota. We found that even before tumors are established there is a shift in microbiota composition. This may be relevant for diagnostic purposes.
In conclusions, in this project we have analyzed how the gut even if continuously exposed to external challenges preserves its integrity and is capable to quickly respond to changes. We found that the control of the well being of the gut derives from complex interactions between immune and non immune cells. We have identified some of the molecular players involved and that may be the target of future intervention in inflammatory bowel diseases. We also found that while the intestinal flora is in general beneficial to the host under certain circumstances it can contribute to promote disease like in intestinal cancers. Together, these finding open new avenues of intervention and prevention.