Epithelial HVEM maintains intraepithelial T cell survival and contributes to host protection

Intraepithelial T cells (IET) provide surveillance of the intestinal epithelium, but little is known about how epithelial-derived signals regulate IET. Analyzing mice with a deficiency for the herpes virus entry mediator (HVEM), a member of the TNF receptor superfamily (TNFRSF14), we showed HVEM maintains the survival of subsets of small intestine IET through interactions with TNFSF14 (LIGHT). RNA-seq and analysis of organoids showed that epithelial cell expressed HVEM provided signals that were required for optimal synthesis of collagen IV. Collagen IV supported IET survival in vitro via interactions with IET β1 integrins. Furthermore, absence of β1 integrin expression in T lymphocytes decreased TCR αβ+ IET in vivo. Intravital microscopy showed that the patrolling movement of all IET was reduced without epithelial HVEM, and we hypothesize that collagen IV interactions with β1 integrins could have been responsible. As likely consequences of decreased total IET number and movement, protective responses to Salmonella enterica were reduced in mice lacking either epithelial HVEM, HVEM binding partners CD160 or LIGHT, or β1 integrins. Therefore, these data defined a circuit whereby epithelial HVEM regulated IET indirectly, through basement membrane synthesis that interacts with T cell integrins, with consequences for mucosal immunity. mRNA from sorted proximal SI IEC or from sorted SI TCRab+CD8aa+ IET from Hvemfl/fl or Villin Cre x Hvemfl/fl mice