Recent pressure to maximize vaccine efficacy has spurred many new discoveries in immunity, revealing numerous paradigms with untapped therapeutic potential.
A growing area of research focuses on tissue-resident memory T cells (TRM cells), a type of immune cell that provides long-lasting protection against pathogens that attack specific organs and tissues.
In a new study published Dec. 28, 2022 at immunityUniversity of California San Diego School of Medicine scientists have revealed a previously unappreciated complexity of TRM cell biology in the gut, which could inspire a new generation of precision therapies against infections, cancer and autoimmune diseases.
After sustaining an infection, the immune system leaves behind memory T cells, which maintain a lasting molecular memory of the pathogen and are ready to sound the alarm should it ever recur.
While some memory T cells are designed to circulate through the bloodstream and provide protection for the entire body, others reside in specific organs and are specialized to fight off pathogens targeting that part of the body.
These TRM cells can provide lifelong immunity to the target tissue, but can also contribute to autoimmune disease if overactivated.
“TRM cells are first responders, right at the front line of infection”said senior author John T. Chang, MD, a professor at UC San Diego School of Medicine.
“Most of our vaccines are designed to provide systemic immunity, but we may be able to achieve even better protection by focusing instead on enhancing the tissue-specific cells that first encounter the pathogen.”
For example, a respiratory virus can be better fought by boosting the TRM cells in the nose and lungs, and a pathogenic intestinal microbe can be better treated by boosting the TRM cells in the gut.
Therefore the goal is to develop therapies that can enhance the formation and maintenance of TRM cells or, in the case of autoimmune diseases, remove the immune cells interrupting these same paths.
Custom immunity
The problem is that scientists still have a lot to learn about what helps TRM cells form and survive, and these rules can be very different in each tissue type.
To explore this, the researchers performed a series of experiments to characterize TRM cells in mice from four different compartments of the intestine: two organs (the small intestine and the colon) and two different layers of tissue in each (the layers intraepithelial and lamina propria).
Experiments revealed that TRM cells in each tissue type displayed distinct patterns of cytokine and granzyme expression, along with substantial transcriptional heterogeneity, epigenetic and functional.
In other words, the same type of immune cells in every part of the gut appeared to be very different in their molecular makeup, function and the chemical signals they depend on.
Further reinforcing this, each cell population also showed differential dependence on Eomesodermin (Eomes), a transcription factor known to influence TRM cell development.
Eomes was canonically thought to repress TRM cells based on previous data gleaned from the skin, liver and kidneys, but new experiments have revealed the opposite to be true in the small intestine.
There, Eomes turned out to be surprisingly important for the survival of TRM cells. However, this was not the case for the colon, highlighting the high context specificity even inside the intestine.
Future research will continue to define the rules of TRM cell formation and maintenance in other tissues and explore what drives their specificity.
For example, the authors suggest that differences in the microbiome of the small intestine and colon may contribute to the unique needs of their TRM cells. then manipulate the microbiome it could be another approach to regulating immune cells in the gut.
“In the future, we want to think about vaccines and other therapies adapted to the specific needs of each organ”said Chang. “By knowing what each tissue type needs to support TRM cell formation and maintenance, we can provide the most efficient immune defenses against disease.”
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