Memory T-Cell Subtypes Implicated in Ulcerative Colitis

By Marilynn Larkin

August 31, 2020

NEW YORK (Reuters Health) - Long-lived, tissue-resident memory T cells may be responsible for the persistent inflammation seen in ulcerative colitis, researchers say.

"The immune system is believed to play a major role in the pathogenesis of inflammatory bowel disease (IBD). However, the types of immune cells involved and their specific contributions to IBD have remained an area of intense research," Dr. John Chang of the University of California, San Diego told Reuters Health by email.

"We observed several subtypes of CD8+ tissue-resident memory T (TRM) cells, a specific class of memory T cell that resides in organs once formed," he said. "One of these tissue-resident memory T cell subtypes (Eomes) was specifically enriched in the intestinal tissues of patients with ulcerative colitis (UC) and programmed to produce large amounts of inflammatory cytokines and other molecules to kill infected cells."

As reported in Science Immunology, Dr. Chang and colleagues used single-cell RNA and antigen (T and B cell) receptor sequencing technologies to investigate key components, cellular states and various lineages of the gastrointestinal mucosal immune system. To do so, they studied cells isolated from blood and rectal biopsies of seven patients with UC and nine healthy controls.

UC was associated with an increase in IgG1+ plasma cells in colonic tissue, increased colonic regulatory T cells characterized by elevated expression of the transcription factor ZEB2 and, as Dr. Chang noted, an enrichment of a gamma delta T cell subset in the peripheral blood.

Further, they observed four transcriptionally distinct subsets of CD8+ TRM cells in colonic tissue across the spectrum of health and disease. Notably, in UC, these subsets showed a greater tendency to differentiate into an inflammatory state, in part by increased expression of the transcription factor Eomesodermin (Eomes).

"Together, these findings suggest the possibility that in UC, upregulation of key factors such as Eomes in intestinal CD8+ TRM cells may promote their conversion into a pathogenic state exhibiting enhanced inflammatory and cytolytic properties," the authors state.

Dr. Chang noted, "Long-lived memory cells are a goal of vaccines against infectious diseases, but these same cells may incite persistent, damaging inflammation in the intestinal tract in the context of IBD."

Gastroenterologist Dr. Jordan Axelrad, assistant professor of medicine at NYU Langone's Inflammatory Bowel Disease Center in New York City, said in an email to Reuters Health that the study adds to current knowledge and points to a potential target for future research.

"Single-cell transcriptomics are critical for the detailed investigation of mechanisms underlying the pathogenesis and maintenance of immune-mediated diseases such as IBD," he affirmed. "In this study, the authors describe several transcriptional changes occurring in adaptive immune cells in UC...and increased expression of Eomesodermin. Novel therapeutic development targeting these cell types and pathways may provide clinical benefit."

That said, "At this point, there is not great clinical relevance," he noted. "However, these cellular and molecular data point to potential biological mechanisms for the clinical heterogeneity in IBD, including distinct phenotypes and behavior."

"Much further work is needed, specifically to understand how therapeutics targeting these individual transcriptomal changes may relate to clinical efficacy," he added. "So, while we are a long way from seeing the direct impact of this work in our clinical practice, it does improve our ability to identify new possible drug targets in IBD."

Dr. Howard Ross, Surgical Director of the Temple Digestive Disease Center at Temple University in Philadelphia, added in an email to Reuters Health, "Though at this minute, there may not be therapies available to take advantage of the findings, knowledge of which components of the immune system are responsible for UC development will lead to targeted therapies. I am certain future work by this group and others will further expand the findings and generate additional treatments."

SOURCE: Science Immunology, online August 21, 2020.