Inflammatory bowel disease (IBD) is a spectrum of gastrointestinal disorders—affecting an estimated six to eight million people worldwide—that result from dysregulated immune responses against gut microbiota. Despite many treatments for IBD, a number of patients fail to respond long-term. In a new study, a team of researchers led by scientists at the University of California, San Diego (UCSD), School of Medicine, reported that the lasting nature of IBD may be due to a type of long-lived immune cell that can provoke persistent, damaging inflammation in the intestinal tract.
The research team integrated single-cell RNA and antigen receptor sequencing from immune cells isolated from samples taken from rectal biopsies or blood of IBD patients and healthy controls. They sought to elucidate key components, cellular states, and clonal relationships of the peripheral and gastrointestinal mucosal immune systems in health and ulcerative colitis (UC).
The work is published in the article, “Heterogeneity and clonal relationships of adaptive immune cells in ulcerative colitis revealed by single-cell analyses,” in Science Immunology.
“We took advantage of a state-of-the-art approach allowing us to generate mRNA and antigen receptor sequencing data from the same single-cells,” said Gene W. Yeo, PhD, professor of cellular and molecular medicine at UCSD School of Medicine, “and analyzed thousands of individual cells, which is quite exciting.”
It has long been believed that immune system dysfunction, in concert with genetic susceptibility and changes in the gut microbiome, plays a significant role in IBD. However, the types of immune cells involved and their specific contributions to IBD have remained unclear. CD8+ T cells are one component of the immune system that identify and kill cells infected by microbial pathogens.
When an infection has been conquered, the immune system leaves behind long-lasting cells called memory T cells, which reside in tissues or circulate through the body remembering past pathogens, ever ready to sound the alarm should specific invaders reappear.
The resulting single-cell sequencing resource revealed heterogeneity among tissue-resident memory T cells (TRM) in UC, with several subtypes of CD8+ tissue-resident memory T (TRM) cells, a specific class of memory cell that resides in organs once formed.
One of these TRM cell subtypes was distinguished by high levels of the transcription factor Eomesodermin and programmed to produce large amounts of cytokines and other molecules to kill newly detected infected cells. The downside is that excessive, persistently high levels of some cytokines can cause inflammation and tissue damage.
“We found that this inflammatory TRM cell subtype seemed to be enriched in the intestinal tissues of patients with ulcerative colitis, a form of IBD that affects the colon,” said John T. Chang, MD, professor of medicine at UCSD School of Medicine. “Long-lived memory cells are a goal of vaccines, but this finding suggests that these same cells, coveted in the fight against infectious diseases, may actually be harmful in the context of IBD.”
The researchers also found evidence that this inflammatory TRM cell subtype might not remain confined to intestinal tissue, but may also escape into the bloodstream.
“This may explain why IBD can affect not just the intestines, but many other parts of the body as well,” said Boland, a gastroenterologist at UCSD Health and assistant adjunct professor of medicine.
Taken together, the authors wrote that these results “provide a detailed atlas of transcriptional changes occurring in adaptive immune cells in the context of UC and suggest a role for CD8+ TRM cells in IBD.” They asserted that identifying this TRM population, and other disease-associated T and B cell subsets, “provides a platform for future functional studies addressing how these subsets conspire to trigger chronic mucosal injury in UC.”
Chang said the findings may help to explain why IBD is chronic and life-long, and point to the possibility of a remedy in the future: Targeting this inflammatory TRM cell subtype for elimination, thus ending the cycle of inflammation and tissue damage.
The researchers noted that much more work is needed to gain a deeper understanding of the role of tissue-resident memory T cells in IBD and to determine whether they can be targeted therapeutically.