How gut cells communicate with and promote survival of T cell guards

Cells in the gut send secret messages to the immune system, and a study by researchers at the La Jolla Institute for Immunology (LJI) has now glimpsed what they’re saying. The research revealed how epithelial cells lining the gut communicate with resident patrolling T cells by expressing a protein called HVEM, which prompts the T cells to survive longer and exercise more to stop potential infections.

“The research shows how barrier cells in the gut, structural elements of the tissue and immune cells present communicate to protect the host,” said LJI Professor and CSO Mitchell Kronenberg, PhD. In the future, Kronenberg and colleagues are interested in investigating the role of HVEM in maintaining a healthy population of gut microbes. Kronenberg said there are signs that a lack of HVEM can affect the composition of the gut microbiome, even in the absence of pathogenic bacteria.

Kronenberg is senior author of the team’s published study in Science Immunologywith the title “Epithelial HVEM maintains intraepithelial T cell survival and contributes to host protection.”

Intestinal intraepithelial lymphocytes (IELs) are one of the largest populations of lymphocytes in the body, the authors explained. “They are found above the basement membrane in the intestinal epithelium and they interact extensively with intestinal epithelial cells (IECs) by actively patrolling the basement membrane and by migrating into the lateral intercellular space.” It is believed that IELs play a critical role in maintaining the integrity of the gut barrier, and for wound repair and protection against pathogens. IELs include innate lymphoid cells (ILCs) “…but are usually T lymphocytes, called intraepithelial T cells (IETs),” the authors continued. “IETs are migrating cells that reside above the basement membrane and patrol them extensively.”

You might imagine the cells lining up like a busy nightclub queue. The epithelial cells are tightly pressed together, while the T-cell guards circulate around the line, patrolling for signs of trouble. “These T cells move around the epithelial cells as if they were actually patrolling,” Kronenberg said.

However, the authors noted that although the IETs remain in close contact with IECs, “how intestinal epithelial cells and basement membrane affect the survival and function of IET, whether in steady state or after infection, is unclear.” What keeps these T cells in the epithelium to do their job? “We have some insight into what gets T cells into the gut, but we need to understand what keeps them there,” Kronenberg said. In fact, many immune cells reside in specific tissues for a long time. By understanding the signals that keep T cells in certain tissues, Kronenberg hopes to shed light on conditions such as inflammatory bowel disease, where far too many inflammatory T cells accumulate in the gut.

Through their new study, the researchers discovered that important signals in the gut are sent through the basement membrane, a thin layer of proteins under the epithelium. In the nightclub scene analogy, the basement membrane would be the sidewalk on which everyone stands. The experiments showed that epithelial cells receive signals via HVEM proteins on their surface that stimulate the synthesis of basement membrane proteins. The findings showed that without HVEM, the epithelial cells could not do their job because they produced less collagen and other structural components needed to maintain a healthy basement membrane.

The results indicated that T cells detect the basement membrane through 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 the epithelium. It’s as if the epithelial cells have written messages on the sidewalk: “Stay here,” “Patrol here,” “Do your job.” The team further explained: “Ligand binding to epithelial HVEM at steady state stimulated the synthesis of extracellular membrane proteins, the most important of which is collagen IV. Collagen IV influenced cell survival by binding to 1 integrins expressed by the Something.” But without an adequate basement membrane, T cells wouldn’t be able to survive or go out on patrol as well.

Using a mouse model, the researchers showed that selectively removing HVEM expression in the gut epithelial cells was a major blow to gut health. Without HVEM, the patrolling T cells could not survive as well, they moved less and were less effective at fighting off infection. When challenged with an invasive strain of Salmonella that causes gastroenteritis, the T cells couldn’t prevent the infection from taking over the gut and spreading to the liver and spleen.

“Intravital microscopy showed that the patrolling motion of IETs was reduced without epithelial HVEM,” the scientist wrote. “As likely consequences of reduced numbers and movement, protective responses to” Salmonella enterica were reduced in mice lacking epithelial HVEM, HVEM ligands, or 1 integrins…”

The results indicated that HVEM of epithelial cells laid the foundation for T cells to guard the gut — the reason they survived in the epithelium — communicating indirectly with the T cells through the basement membrane. “Here we showed that HVEM expressed by small intestinal epithelial (SI) cells was involved in the homeostasis of natural IETs, the patrolling function of steady-state IETs and the response to pathogenic bacteria,” the team further noted. “Therefore, the data show how epithelial responses affecting the basement membrane, a structural element of tissue, integrate to regulate tissue-resident T cells in the gut at steady state and after infection.”

The experiments were led by the study’s first authors, Goo-Young Seo, PhD, an instructor at LJI, and Daisuke Takahashi, PhD, formerly of LJI and now at Keio University in Tokyo. The team worked closely with the lab of LJI Professor Hilde Cheroutre, PhD, the LJI Microscopy Core, the LJI Flow Cytometry Core, and used intra-vital imaging RNA sequencing techniques to investigate the role of HVEM in the gut.

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