# HVEM: A TNF family receptor that influences mucosal immunity and the microbiome

> **NIH NIH U01** · LA JOLLA INSTITUTE FOR IMMUNOLOGY · 2020 · $535,300

## Abstract

Summary
The herpes virus entry mediator (HVEM) is a member of the TNF receptor super family. Our published
findings indicated that HVEM expressed by mucosal epithelial cells is important for innate defense
against pathogenic bacteria in the intestine and the lung. Our recent work suggests that HVEM also
functions in intestine epithelial cells under steady state conditions. Mice with an epithelial cell-specific
HVEM deletion have a decrease in the survival of intraepithelial lymphocytes (IEL) in the small intestine,
and an increase in segmented filamentous bacteria (SFB), which causes an increase in Th17 cells. The
experiments in this application are designed to explore the mechanistic bases for the effects of HVEM on
immune and microbial homeostasis in the intestine, and the connection, if any, between decreased IEL
populations and increased SFB. HVEM has three binding partners: CD160, BTLA, and LIGHT. In
specific aim 1, we will use mice with germ line or conditional deficiency for the genes encoding each of
these molecules to identify which one(s) is relevant and which cell type expresses this protein. In
specific aim 2, we will investigate how epithelial HVEM regulates the size of the IEL population. Our
preliminary data suggest an indirect mechanism, in which HVEM signals cause the epithelium to
increase synthesis of basement membrane proteins that bind to β1-containing integrins expressed by the
IEL. The integrin-basement membrane interaction leads to increased IEL survival. We will test this
indirect mechanism, in part by analyzing IEL from β1 integrin deficient mice. As an alternative
mechanism, we will investigate if HVEM acts as a ligand that carries out reverse signals that promote
survival directly back to IEL through one of its binding partners. In specific aim 3, we will determine if the
decrease in IEL and increase in SFB in the absence of epithelial HVEM are causally linked. We also will
carry out in vitro and in vivo experiments to understand how epithelial HVEM affects the microbiome, in
particular if there are effects on the IL-23-IL-22 axis and type 3 innate lymphoid cells (ILC3), and using
organoid cultures, we will determine if signals through NF-κB and/or Stat3 are relevant. Overall, these
experiments will provide a deeper understanding of the function of the numerous resident, innate-like
lymphocytes in the intestine, the cross talk between resident lymphocytes and epithelial cells, and how
these molecular and cellular interactions contribute to tissue homeostasis and the microbiome. The
increase in Th17 cells in the intestine of mice lacking epithelial HVEM, and the association of HVEM
polymorphisms with inflammatory diseases in the intestine, indicate that the fundamental issues
addressed in this application are important for understanding the function of the mucosal immune system
in providing protection while avoiding destructive inflammation.

## Key facts

- **NIH application ID:** 9936310
- **Project number:** 5U01AI125955-05
- **Recipient organization:** LA JOLLA INSTITUTE FOR IMMUNOLOGY
- **Principal Investigator:** MITCHELL KRONENBERG
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $535,300
- **Award type:** 5
- **Project period:** 2016-06-13 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936310

## Citation

> US National Institutes of Health, RePORTER application 9936310, HVEM: A TNF family receptor that influences mucosal immunity and the microbiome (5U01AI125955-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9936310. Licensed CC0.

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