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Exciting new look at what makes T cells protect the gut – ScienceDaily


Cells in the gut send secret messages to the immune system. Thanks to new research from scientists at the La Jolla Institute of Immunology (LJI), we can finally understand what they’re saying.

A new study in Science Immunology shows how the barrier cells that line the gut send messages to the patrolling T cells that reside there. These cells interact by expressing a protein called HVEM, which causes the T cells to survive longer and move more to stop potential infections.

“The study shows how barrier cells in the gut, structural elements of the tissue, and resident immune cells interact to provide host protection,” says LJI Professor and Principal Investigator Mitchell Cronenberg, Ph.D., senior author of the new study.

Barrier cells, or “epithelial” cells, form a thick single-cell layer that lines the intestine. One can imagine these cells lining up like a busy queue outside a nightclub. Epithelial cells fuse together. They push each other and chatter. Meanwhile, T-cell guards circulate around the line, scanning the block for signs of trouble. “These T cells move around the epithelial cells as if they were actually patrolling,” Cronenberg says.

But what makes these T cells in the epithelium do their job?

“We have some idea of ​​what gets T cells to the gut, but we need to understand what keeps them there,” Cronenberg says. In fact, many immune cells reside in certain tissues for a long time. By understanding the signals that keep T cells in certain tissues, Cronenberg hopes to shed light on diseases such as inflammatory bowel disease, where too many inflammatory T cells accumulate in the gut.

In a new study, researchers have found that important signals in the gut are transmitted 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 discovered that without HVEM, epithelial cells cannot do their job because they produce less collagen and other structural components needed to maintain a healthy basement membrane.

T cells detect the basement membrane through the adhesion molecules they express on their surface, called integrins. The interaction of T cell integrins with basement membrane proteins facilitates the transmission of messages that enable T cells to survive and patrol the epithelium. It’s as if epithelial cells wrote messages on the pavement: “Stay here”, “Patrol here”, “Do your job”. Without a sufficient basement membrane, T cells would not be able to survive or go on patrol.

Using a mouse model, the researchers showed that removing HVEM expression—only in intestinal epithelial cells—was a major blow to gut health. Patrolling T cells could not survive, and they did not move around as much. Those T cells made lousy guards. When calling Salmonella typhimurium, an invasive bacterium that causes gastroenteritis, the T cells allowed the infection to take over the intestine and spread to the liver and spleen. Thus, HVEM from epithelial cells laid the foundation for gut-protecting T cells—which is precisely why they survived in the epithelium—by indirectly binding to T cells through the basement membrane.

These insights came from a series of experiments initiated by the study’s first authors Gu-Yang Seo, Ph.D., instructor at LJI, and Daisuke Takahashi, Ph.D., formerly of LJI and now at Keio University in Tokyo. The team worked closely with the laboratory of LJI Professor Hilde Scherutre, Ph.D., the LJI Center for Microscopy, the LJI Flow Cytometry Center and used in vivo imaging RNA sequencing techniques to investigate the role of HVEM in the gut.

Looking ahead, Cronenberg and his colleagues are interested in investigating the role of HVEM in maintaining a healthy population of gut microbes. Cronenberg says there are indications that a lack of HVEM can affect the composition of the gut microbiome even in the absence of pathogenic bacteria.

Additional authors of the study “Epithelial HVEM Supports Intraepithelial T Cell Survival and Promotes Host Defense” include Qingyang Wang, Zbigniew Mikulski, Angeline Chen, Ting-Fang Chou, Paola Marcovecchio, Sara McArdle, Ashu Sethi, Jr-Wen Shui, Masumi1 Takahashi, Charles D. Surh, and Hilde Cherutr.

This research was supported by the National Institutes of Health (grants P01 DK46763, R01 AI61516, and MIST U01, AI125955, MIST U01 AI125957, S10RR027366, and S10OD021831), the Crohn’s and Colitis Foundation of America (grant CCFA-254582), the Uehrari Foundation, and a Chan-Zuckerberg Initiative grant Imaging Scientist.

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