Mechanisms of Mucosal Th17 Cell Induction By Segmented Filamentous Bacteria

点击翻译按钮获取中文摘要

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.