Dietary fiber and Segmented Filamentous Bacteria interaction with intestinal epithelial cells supports the development of CD4 +CD8αα +intraepithelial T cells

Abstract

Abstract Double positive intraepithelial lymphocytes (DP IELs) are microbiome induced CD4 +CD8αα +T cells that play a role in maintaining homeostasis and reducing inflammation in the small intestine. While the impact of the microbiome on the intestinal immune system has been extensively studied, little is known about how changes in macronutrients, such as dietary fiber, affect the development of important immune cell populations through changes in the microbiome. Here we show that a diet low in fermentable fiber (LFF) impairs development of DP IELs by reducing MHC-II expression on intestinal epithelial cells (IECs). Bulk RNA sequencing of ileal IECs revealed that LFF fed mice had lower expression of genes associated with the antigen presentation machinery. Subsequently, flow cytometry analysis confirmed increased expression of MHC-II on IECs in standard chow fed mice, which is required for DP IEL development. 16s rRNA sequencing of the microbiota of LFF mice showed that SFB is reduced in these animals. We found that colonizing mice with SFB induces MHC-II expression on IECs and restores development of DP IELs in a fiber-dependent manner. Finally, using the offspring of mice that naturally harbor SFB, we show that MHC-II expression on IECs and IFN-γ levels in the ileum increase gradually over time and correlate with SFB colonization. These results suggest that dietary fiber is required for the development of DP IELs through supporting SFB colonization and increasing expression of MHC-II on small intestinal epithelial cells. Supported by grants from NIH (1R011DK129950) and startup funds from Emory University