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Single-Cell Analysis Reveals Ulcerative Colitis Tissue, Immune Features

NEW YORK – A University of California at San Diego- and VA San Diego Healthcare System (VASDHS)-led team has used a volley of transcriptomic and antigen receptor sequencing strategies to characterize tissue and immune cell features in individuals with or without ulcerative colitis, a form of inflammatory bowel disease (IBD).

"Overall, our work has resulted in an integrated single-cell transcriptomic and antigen receptor sequencing dataset that expands the single-cell data available in human IBD," co-senior authors John Chang, with UCSD and VASDHS, and Gene Yeo, a UCSD cellular and molecular medicine researcher with ties to the center's Institute for Genomic Medicine, and their co-authors wrote in a Science Immunology paper published on Friday, adding that the study "is likely to accelerate mechanistic and functional investigations into the role of specific genes in relevant immune cell types and states in [ulcerative colitis]."

Using a combination of fluorescence-activated cell sorting, single-cell RNA sequencing, single-cell T cell receptor sequencing (scTCR-seq), single-cell B cell receptor sequencing (scBCR-seq), and other approaches, the researchers assessed blood and gastrointestinal mucosal samples from seven individuals with ulcerative colitis and nine unaffected controls. They documented a suite of ulcerative colitis-related immune cell shifts and clonal relationships — from clonal B cell receptor clonotype clusters and an uptick in plasma cells expressing immunoglobulin G1 to a rise in ZEB2 transcription factor-expressing regulatory T cells in colon tissue.

The team also flagged informative transcriptional features in CD8+ tissue-resident memory T cells typically tasked with buffeting bacterial infections, defining a handful of transcriptionally distinct clusters of the cells in colon tissue that differed from healthy tissue to tissue affected by ulcerative colitis, including a cluster with more inflamed versions of the CD8+ tissue-resident T cells.

"It is well established that [tissue-resident memory T] cells mediate protective responses to microbial infection, but a potentially pathogenic role for these cells in autoimmune and inflammatory diseases has been increasingly appreciated," the authors wrote, noting that their results revealed CD8+ tissue-resident memory T cell clusters with shared T cell receptor clonotype features, suggesting they stem from distinct states of the same cell type.

Among the transcriptional and cellular shifts identified in blood samples from those with active ulcerative colitis, meanwhile, the team reported higher-than-usual levels of T cells with gamma delta T cell receptor features, hinting at possible ties between this T cell subset and disease features.

In contrast to tissue and immune analyses based on bulk tissue samples from individuals with ulcerative colitis and other forms of IBD, the team reasoned that the single cell- and antigen receptor-centered strategies may uncover relatively subtle cell signatures that might otherwise be masked by signals from more prominent cell types.

"[I]ntestinal tissue is heterogeneous, composed of diverse epithelial, stromal, and immune cells, and it has been increasingly appreciated that substantial heterogeneity can exist even within the same immune cell type," the authors explained. "Our integrated single-cell transcriptomic and antigen receptor sequencing analyses have resulted in several insights into the immunobiology of [ulcerative colitis]."

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