San Diego [US]: Recent push to increase vaccine effectiveness has sparked numerous novel immunological findings, exposing numerous paradigms with unrealized therapeutic potential. Tissue-Resident Memory T cells (TRM cells), an immune cell type that offers long-lasting defence against pathogens attacking particular organs and tissues, are the subject of one expanding area of research.
Researchers from the University of California San Diego School of Medicine revealed a previously underappreciated complexity of TRM cell biology in the gut in a new study that was published on December 28, 2022, in Immunity. This finding may inspire a new generation of precision therapeutics against infection, cancer, and autoimmune disease.
The immune system leaves behind memory T cells after an infection, which keeps a long-lasting molecular memory of the pathogen and is prepared to raise the alarm if it ever reappears. While some memory T cells are created to circulate throughout the bloodstream and offer total body defence, others live in certain organs and are trained to combat viruses that specifically target those organs. These TRM cells can give the target tissue lifelong immunity, but if overactivated, they can potentially lead to autoimmune disorders.
"TRM cells are the first responders, right at the front lines of infection," said senior author John T. Chang, MD, professor at UC San Diego School of Medicine. "Most of our vaccines are designed to provide systemic immunity, but we may be able to get even better protection by instead focusing on boosting the tissue-specific cells that encounter the pathogen first."
For example, a respiratory virus may be best fought by strengthening TRM cells in the nose and lungs, and a pathogenic gut microbe best treated by enhancing TRM cells in the intestines. Thus the goal is to develop therapeutics that could boost the formation and maintenance of TRM cells, or in the case of autoimmune disease, remove the immune cells by disrupting these same pathways.
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The issue is, scientists still have a lot to learn about what helps TRM cells form and survive, and these rules may be quite 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 gut: two organs (the small intestine and the colon) and two different tissue layers in each (the intraepithelial and lamina propria layers).
The experiments revealed that TRM cells in each tissue type exhibited distinct patterns of cytokine and granzyme expression, along with substantial transcriptional, epigenetic and functional heterogeneity. In other words, the same type of immune cells in each part of the gut appeared to be very different in their molecular makeup, function and chemical signals they depend on.
Reinforcing this further, each population of cells also showed differential dependence on Eomesodermin (Eomes), a transcriptional factor known to affect TRM cell development. Eomes was canonically thought to repress TRM cells based on previous data collected from the skin, liver and kidney, but the new experiments revealed the opposite was true in the small intestine. There, Eomes proved to be surprisingly important in the survival of TRM cells. However, this was not the case in the colon, highlighting the high context-specificity even within the gut.
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 the colon may contribute to the unique needs of their TRM cells, so manipulating the microbiome may be another approach to regulating immune cells in the gut.
"In the future, we want to be thinking about vaccines and other therapeutics that are tailored to the specific needs of each organ," said Chang. "By knowing what each tissue type needs to support the formation and maintenance of TRM cells, we can provide the most efficient immune defences against disease." (ANI)
