Your instinct is a battlefield. The cells that line the small intestine have to balance two seemingly contradictory functions: absorbing nutrients from food while also keeping an eye out for pathogens trying to invade the body.
“This is a surface where pathogens can sneak in,” says La Jolla Institute of Immunology (LJI) assistant professor Miguel Reina-Campos, Ph.D. “That’s a huge challenge for the immune system.”
So how do immune cells keep the gut safe? New research led by scientists at LJI, UC San Diego, and the Allen Institute for Immunology shows that pathogen-fighting immune cells called tissue-resident memory CD8 T cells (TRM cells) undergo a surprising transformation (and relocation) as they fight infections in the small intestine.
In fact, these cells literally rise higher in the tissue to fight infections before pathogens can spread to deeper, more vulnerable areas.
“Gut tissue has evolved to provide signals to immune cell infiltrates, to place immune cells in specific locations so that they have a better ability to stop pathogens,” says Reina-Campos, first author of the new study. Nature study along with co-author Alexander Monell of UC San Diego and co-senior authors Maximilian Heeg, M.D., and Ananda W. Goldrath, Ph.D., of the Allen Institute for Immunology and UC San Diego.
The new findings add to the growing body of evidence that immune cells adapt to protect specific tissues. Reina-Campos believes these “tissue-resident” immune cells may be key players in future cancer immunotherapies targeting tumors in specific organs.
T cells in motion
Reina-Campos and his colleagues investigated the formation of TRM cells in the small intestine. The team took advantage of a cutting-edge technology called spatial transcriptomics to track these cells in both human and mouse tissue samples.
Their work showed that the small intestine contains two types of TRM cells. These cells divide between the tiny finger-like “villi” structures that line the small intestine or the “crypts” between the protruding villi.
The researchers found that the progenitor-like TRM The cells live closer to the crypts between the villi. On the other hand, differentiated TRM They occupy more exposed regions in the upper part of the villi. “Differentiated immune cells are most exposed at the top of the villi, and that’s where they have the best ability to protect you from infections,” says Reina-Campos.
Meanwhile, a reserve population of progenitor-like TRM The cells are still low in the crypts. “These cells can replenish the pool of effector T cells, so the immune system keeps them as backup in the deeper parts of the tissue,” adds Reina-Campos.
What keeps these populations organized and under control?
To spy on these important immune cells within their natural habitat, Reina-Campos and his colleagues used a new technology, called spatial transcriptomics, to observe millions of messenger RNA molecules simultaneously with subcellular resolution.
“For the first time we were able to capture the formation of immunological memory in space and time,” says Reina-Campos.
By looking at the small intestine after a viral infection, scientists discovered that the intestine releases chemical signals to tell immune cells where to go and what to do. “This study offers a new resource to find signals that position immune residents to strengthen our intestinal immunity,” says Reina-Campos.
Checkmate due to illness?
Reina-Campos credits his mentor, Goldrath, as well as the expertise of Heeg and Monell for making this study possible. As Reina-Campos explains, Heeg and Monell developed new computational approaches to make sense of the enormous amounts of data captured through spatial transcriptomics.
“It has represented a great advance in our ability to observe hundreds or thousands of genes simultaneously in intact tissues,” says Reina-Campos. “With this study, we have opened a new path for discovery.”
Reina-Campos compares the battle between immune cells and pathogens to a game of chess.
“To be a chess grandmaster, you not only need to know about the pieces: the bishops, pawns, rooks, etc., but also how they move together on the chess board,” he says.
Scientists have long studied chess pieces (by analyzing cells taken from tissue), but they have not been able to get a good look at the chess game itself. “We don’t know much about how the chess board works, and we know even less about the rules that apply to our chess pieces as they move around the board,” says Reina-Campos.
The new study gives researchers detailed insight into how immune cells interact with each other and with their cell board.
Reina-Campos says the new finding should guide future research into how immune cells develop and move through other organs with different tissue structures, such as the kidneys and lungs, and how immune cells might fight tumors in these organs.