How resident gut bacteria engage adaptive immunity is not clear. Commensal specific T cells are difficult to detect in the LP and multiple mechanisms have been described that prevent development of such cells at steady state. These include sequestration in the lumen and immunological ignorance, re-direction of commensal-specific T cells into the Treg compartment, and negative selection by type 3 innate lymphoide cells (ILC3). We have identified an example of commensal-host interaction in which segmented filamentous bacteria (SFB) induce an antigen-specific non-inflammatory Th17 cell response. Therefore, certain commensals do engage adaptive immunity and generate effector T cells that are apparently non-inflammatory. The mechanisms involved in this process are not known, but are of significant interest, because they may help design strategies to curb inflammatory potential of effector T cells, while preserving their effector function. We also showed that this process occurs through a unique antigen-presentation pathway that requires intestinal macrophages (Mfs). Here we propose to investigate the mechanistic role of intestinal Mfs as well as the pathogenicity of the induced Th17 cells. We also show that intestinal epithelial cells are involved in the crosstalk between the bacteria and Mfs, and will investigate a novel potential mechanism of this interaction. We will investigate the following specific aims: 1) we will identify the innate immune subset presenting SFB antigens; 2) we will characterize the co- operative role of intestinal epithelial cells, Mfs and dendritic cells in generating Th17 cells; 3) we will investigate the pathogenicity of the generated Th17 cells and identify genes that regulate their ability to cause inflammation; 4) we will examine whether a similar antigen-presentation pathway is involved in induction of Th17 cells by human commensal bacteria.
T helper 17 (Th17) cells can be non-pathogenic and provide protection against mucosal infections or pathogenic and contribute to chronic inflammatory conditions, such as inflammatory bowel diseases (IBD); however what controls Th17 cell pathogenicity is not known. Non-pathogenic Th17 cells in the gut are induced by commensal bacteria and, specifically, by segmented filamentous bacteria (SFB) by, as yet, unknown mechanisms. In this proposal we have designed studies to understand how intestinal macrophages and intestinal epithelial cells participate in this process, which will identify these cells as specific cellular targets for regulating Th17 cell pathogenicity in the gut in order to control immune responses.
| Ivanov, Ivaylo I (2017) Mucosal Bioengineering: Gut in a Dish. Trends Immunol 38:537-539 |
| Ivanov, Ivaylo I (2017) Microbe Hunting Hits Home. Cell Host Microbe 21:282-285 |
| Sisirak, Vanja; Sally, Benjamin; D'Agati, Vivette et al. (2016) Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity. Cell 166:88-101 |
| Farkas, Adam M; Ivanov, Ivaylo I (2015) Escaping Negative Selection: ILC You in the Gut. Immunity 43:12-4 |
| Atarashi, Koji; Tanoue, Takeshi; Ando, Minoru et al. (2015) Th17 Cell Induction by Adhesion of Microbes to Intestinal Epithelial Cells. Cell 163:367-80 |
| Panea, Casandra; Farkas, Adam M; Goto, Yoshiyuki et al. (2015) Intestinal Monocyte-Derived Macrophages Control Commensal-Specific Th17 Responses. Cell Rep 12:1314-24 |
| Sun, Jianbo; Wang, Jiguang; Pefanis, Evangelos et al. (2015) Transcriptomics Identify CD9 as a Marker of Murine IL-10-Competent Regulatory B Cells. Cell Rep 13:1110-1117 |
| Farkas, Adam M; Panea, Casandra; Goto, Yoshiyuki et al. (2015) Induction of Th17 cells by segmented filamentous bacteria in the murine intestine. J Immunol Methods 421:104-111 |
| Goto, Yoshiyuki; Obata, Takashi; Kunisawa, Jun et al. (2014) Innate lymphoid cells regulate intestinal epithelial cell glycosylation. Science 345:1254009 |
| Goto, Yoshiyuki; Panea, Casandra; Nakato, Gaku et al. (2014) Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity 40:594-607 |
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