Study Uncovers Messaging System Between Gut Cells and Immune System

Researchers at the La Jolla Institute for Immunology (LJI) have uncovered a mechanism the gut uses to help immune system “patrol” cells both survive and locate pathogens.

The work focused on how barrier, or "epithelial" cells, that form a one-cell thick layer lining the gut communicate with structure elements of the tissue and resident immune cells to provide host defense. The epithelial cells are tightly packed and exchange messages, while immune system T cells act like security guards, circulating to detect signs of trouble. "These T cells move around the epithelial cells as if they are truly patrolling," says LJI Professor and Chief Scientific Officer Mitchell Kronenberg, Ph.D., senior author of the new study published in Science Immunology.

They found that these barrier cells send messages to the patrolling T cells by expressing a protein called HVEM, which prompts T cells to survive longer and move more to stop potential infections.

"We've got some insight on what gets T cells to the gut, but we need to understand what keeps them there," says Kronenberg. In fact, a lot of immune cells reside long-term in specific tissues. By understanding the signals that keep T cells in certain tissues, Kronenberg hopes to shed light on conditions like inflammatory bowel disease, where far too many inflammatory T cells gather in the bowel.

The study found that important signals in the gut are sent through the basement membrane, a thin layer of proteins beneath the epithelium. Their experiments show that epithelial cells receive signals through HVEM proteins on their surface that stimulate synthesis of basement membrane proteins. The team found that without HVEM, the epithelial cells couldn't do their job because they produced less collagen and other structural components needed to maintain a healthy basement membrane.

T cells detect the basement membrane via adhesion molecules they express on their surface, called integrins. The interaction of the T cell integrins with the basement membrane proteins promotes messages that allow the T cells to survive and patrol in the epithelium.  It is as if the epithelial cells have written messages on the sidewalk: "Stay here," "Patrol here," "Do your job."   Without a sufficient basement membrane, T cells could not survive as well or go on patrol.

Using a mouse model, the researchers then showed that removing HVEM expression—only in the gut epithelial cells—was a major blow to gut health. Patrolling T cells could not survive as well and they didn't move as much. These T cells made lousy security guards. When challenged with Salmonella typhimurium, an invasive bacterium that causes gastroenteritis,  the T cells allowed the infection to take over the intestines and spread to the liver and spleen.  Therefore, HVEM from epithelial cells laid the groundwork for T cells to guard the gut—it was the very reason they survived in the epithelium—communicating with the T cells indirectly through the basement membrane.

Going forward, Kronenberg and his colleagues are interested in investigating the role of HVEM in maintaining a healthy population of gut microbes. Kronenberg says there are signs that a lack of HVEM can sway the composition of the gut microbiome even in the absence of pathogenic bacteria.