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The small intestine is a unique environment. As food moves through the gut, the cells lining this tissue face the dual challenge of absorbing nutrients while defending against invading pathogens. Research from the La Jolla Institute for Immunology (LJI), UC San Diego, and the Allen Institute for Immunology has uncovered how a specific type of immune cell, tissue-resident memory CD8 T cells (TRM cells), adapts its behavior to safeguard this critical barrier.
The study, published in Nature, reveals that TRM cells in the small intestine undergo a strategic transformation—changing their location within the tissue to defend against infection before pathogens can penetrate deeper and more vulnerable layers.
"This is a surface where pathogens can sneak in," said Miguel Reina-Campos, an assistant professor at LJI and co-first author of the study. "That’s a massive challenge for the immune system."
Mapping T Cells in the Small Intestine
The small intestine is lined with tiny, finger-like villi and deeper crypts between these structures. Reina-Campos and his team examined TRM cells in both human and mouse samples around these structures. Their findings reveal that TRM cells are split into two distinct populations. Progenitor-like TRM cells reside in the crypts, while more differentiated TRM cells are positioned at the tops of the villi.
“Differentiated immune cells are more exposed at the top of the villi, and that’s where they have a better ability to protect you from infections,” Reina-Campos explained. The crypt-dwelling progenitor-like cells serve as backups, ready to replenish effector T cells when needed.
This spatial organization is maintained by chemical signals released by the gut, which guide TRM cells to their proper locations. "The tissue in the gut has evolved to provide signals to immune cell infiltrates—to put immune cells in specific places so they have a better ability to stop pathogens," Reina-Campos added.
The Role of Spatial Transcriptomics
Central to this study was spatial transcriptomics, a technology capable of capturing messenger RNA activity across intact tissue samples at subcellular resolution. This approach allowed the team to visualize how TRM cells develop and respond to infection.
"For the first time, we were able to capture the formation of immunological memory in space and time," Reina-Campos noted. The data generated through this technique offers researchers a detailed map of immune cell behavior, helping to uncover how these cells interact within their environment.
Reina-Campos credited his collaborators, including co-first author Alexander Monell and co-senior authors Maximilian Heeg and Ananda Goldrath, for their computational expertise in analyzing the vast dataset. “It’s led to a breakthrough in our ability to look at hundreds to thousands of genes simultaneously in intact tissues,” he said. "With this study, we've opened up a new path for discovery."
Broader Implications for Immunology
While the work is far from complete, Reina-Campos and his team’s findings provide a foundation for exploring how immune cells function across various tissues. He believes the insights gained here could inform research into other organs, such as the kidneys or lungs, which have their own unique tissue structures.
Reina-Campos also likened the immune system’s response to a chess match, where understanding not just the pieces but their interactions on the board is crucial. For many years, researchers have focused on the chess pieces through the analysis of cells extracted from tissue, but they haven’t taken a closer look at the chess match itself. "We don't know as much about how the chessboard works—and we know even less about the rules that apply to our chess pieces as they move across the board," stated Reina-Campos.
Publication Details
Reina-Campos, M., Monell, A., Ferry, A. et al. Tissue-resident memory CD8 T cell diversity is spatiotemporally imprinted. Nature (2025). https://doi.org/10.1038/s41586-024-08466-x