A new study in Science Immunology reveals how the barrier cells that line the intestines send messages to the patrolling T cells that reside there. These cells communicate by expressing a protein called HVEM, which prompts T cells to survive longer and move more to stop potential infections.
Barrier cells, or “epithelial” cells, form a one-cell thick layer that lines the gut. One can picture these cells lining up like a busy queue outside a nightclub. The epithelial cells squish together. They jostle each other and chat. Meanwhile, T cell security guards circulate around the line, looking up and down the block for signs of trouble. “These T cells move around the epithelial cells as if they are truly patrolling,” says Kronenberg.
But what keeps these T cells in the epithelium to do their job?
“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.
In the new study, the researchers found that important signals in the gut are sent through the basement membrane, a thin layer of proteins beneath the epithelium. In our nightclub scene, the basement membrane would be the sidewalk where everyone stands.
Their experiments show that epithelial cells receive signals through HVEM proteins on their surface that stimulate the 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.
Mitchell Kronenberg et. al, Epithelial HVEM maintains intraepithelial T cell survival and contributes to host protection, Science Immunology, 29-Jul-2022, DOI: 10.1126/sciimmunol.abm6931