CD160-HVEM signaling in intestinal epithelial cells modulates gut microbial homeostasis

Abstract

Abstract Intestinal epithelial cells (IEC) are a first barrier that segregates host and commensal bacteria to maintain intestinal homeostasis. Intestinal intraepithelial lymphocytes (IEL) are located beneath or between adjacent IEC and directly contact IEC. The herpes virus entry mediator (HVEM), a member of the tumor necrosis factor receptor superfamily (TNFRSF), is highly expressed by IEC. Epithelial HVEM expression was previously reported as a regulator of innate immune defense during acute infections in the intestine (Shui et al., Nature, 2012). Here, we identify that HVEM signaling in IEC is important for the regulation of the gut microbiota at steady state. Mice with an epithelial-specific deletion of the gene encoding HVEM (HvemΔIEC) had significantly increased segmented filamentous bacteria (SFB) which caused an increase in Th17 cells in the ileum. Treatment with the antibiotic vancomycin eliminated SFB and decreased Th17 cells in HvemΔIEC mice. Additionally, mice with a deletion of the gene encoding CD160, which is a ligand for HVEM and is highly expressed by IEL, including intraepithelial innate lymphoid cells (ILC) and intraepithelial T cells, had increased SFB in the ileum. Our findings suggest that the interaction of CD160 expressed by IEL with HVEM expressed by IEC is important at steady state for shaping the microbiota in the intestine.