Pathogen-fighting immune cells known as tissue-resident memory CD8 T cells (TRM cells) experience surprising shifts and movements when responding to infections in the small intestine.
The gut serves as a crucial frontline. The cells lining the small intestine must perform two vital tasks: absorbing nutrients from food while actively defending against incoming pathogens.
“This area is a point of easy entry for pathogens,” says Miguel Reina-Campos, Ph.D., an Assistant Professor at the La Jolla Institute for Immunology (LJI). “This poses a major challenge for the immune system.”
How do immune cells ensure safety in the gut? Recent research from a collaborative effort between LJI, UC San Diego, and the Allen Institute for Immunology shows that TRM cells undergo significant changes and reposition themselves in response to infections in the small intestine.
These immune cells actually rise to higher regions within the tissue to fight infections before pathogens can move into more sensitive areas.
“The gut tissue has evolved to emit specific signals to guide immune cell infiltrates, placing them in ideal positions to effectively counteract pathogens,” explains Reina-Campos, who is the lead author of the new Nature study, alongside co-lead author Alexander Monell from UC San Diego and co-senior authors Maximilian Heeg, M.D., and Ananda W. Goldrath, Ph.D., from the Allen Institute for Immunology and UC San Diego.
This research enhances our understanding of how immune cells adjust to protect specific tissues. Reina-Campos believes that these “tissue-resident” immune cells could be pivotal in future cancer treatments targeting tumors in specific organs.
T Cells in Action
Reina-Campos and his team investigated how TRM cells develop in the small intestine. They used advanced spatial transcriptomics technology to study these cells in both human and mouse tissue samples.
Their findings revealed two types of TRM cells within the small intestine. They are situated in either the small, finger-like “villi” structures lining the intestine or the “crypts” found between the villi.
The researchers noted that progenitor-like TRM cells are located closer to the crypts, while differentiated TRM cells are found in the more exposed regions at the tips of the villi. “The differentiated immune cells are more prominent at the top of the villi, which enhances their ability to defend against infections,” says Reina-Campos.
Furthermore, a reserve of progenitor-like TRM cells is maintained in the crypts, ready to replenish the effector T cell populations as necessary, according to Reina-Campos.
What regulates and organizes these cell populations?
To study these critical immune cells in their natural environments, Reina-Campos and his team employed spatial transcriptomics to assess millions of messenger RNA molecules at a subcellular level.
“For the first time, we could visualize the development of immunological memory both spatially and temporally,” says Reina-Campos.
After examining the intestines following a viral infection, the researchers found that the gut produces chemical signals that guide immune cells in their functions and movements. “This study offers fresh insights into the signals that help coordinate immune residents, improving gut immunity,” states Reina-Campos.
A Strategic Move Against Disease?
Reina-Campos expresses gratitude for the mentorship of Goldrath and the expertise of Heeg and Monell, which were crucial for this study. Heeg and Monell created new computational techniques to analyze the extensive data collected through spatial transcriptomics.
“This has significantly advanced our ability to analyze hundreds or thousands of genes simultaneously within intact tissues,” says Reina-Campos. “With this research, we’ve opened the door to new discoveries.”
Reina-Campos compares the interaction between immune cells and pathogens to a chess match.
“Becoming a chess grandmaster requires understanding not only the pieces—like bishops, pawns, and rooks—but also their coordinated movements on the board,” he explains.
For many years, researchers have focused on the pieces by examining cells extracted from tissues but have lacked a complete understanding of the game’s dynamics. “We do not fully comprehend how the chessboard functions and even less about the rules governing our chess pieces’ movements,” Reina-Campos observes.
This new study provides valuable insights into how immune cells interact with each other and their surroundings.
Reina-Campos emphasizes that these findings should guide future research on how immune cells develop and navigate through various organs with distinct tissue architectures, like the kidneys and lungs, and how they might fight tumors in these regions.
