Research finds stem-like T cells are associated with pathogenesis in ulcerative colitis

By Pooja Toshniwal PahariaReviewed by Danielle Ellis, B.Sc.Jun 21 2024

In a recent study published in Nature Immunology, researchers investigated whether stem-like T lymphocytes are involved in ulcerative colitis (UC) pathogenesis.

Background

UC is an inflammatory illness presenting with T-lymphocyte-mediated inflammation frequently provoked by microbial antigens. Despite the success of authorized medications, many patients do not react, indicating that existing treatments may not sufficiently target pathogenic immunological cell types and their effector chemicals.

Studies have identified significant links between particular colonic T lymphocyte subsets and ulcerative colitis, with some indicating the role of homologous types of T lymphocytes in disease pathogenesis. Recent investigations in murine autoimmune illness models have revealed stem-type autoimmune progenitor helper T lymphocytes secreting cluster of differentiation 4 (CD4+) and cytotoxic CD8+ T lymphocytes that express T cell factor 1 (TCF1).

About the study

The present study researchers explored stem-like T lymphocyte involvement in UC pathophysiology.

The researchers acquired UC patient samples from endoscopically inflamed sigmoid colonic tissue and more proximal non-inflamed colonic tissue with no known impacted tissue when accessible. They also collected sigmoid colon samples from individuals in remission from locations of past inflammation.

Samples were obtained from healthy controls with no gastrointestinal signs and symptoms and underwent endoscopic examinations for prior colonic polyps or iron deficiency-type anemia. They excluded patients having histories of cancer, immunosuppressive treatment, or polyposis syndrome.

The researchers examined colonic T lymphocytes extracted from UC patients and controls, concentrating on evidence demonstrating stem-like T lymphocyte presence in colon tissue and their interactions with other probably pathogenic T lymphocyte subsets within the colon.

They also performed single-cell transcriptomic analysis of sorted lymphocytes extracted from endoscopically non-inflamed and inflamed colonic tissues of individuals with active ulcerative colitis, both sexes, who had never received biological therapy.

The researchers used cellular indexing of transcriptomes and epitopes with sequencing (CITE-seq) to mark cells expressing CD4 and CD8α. They assessed published one-cell data from UC patients to test the validity of the study results in other cohorts. They investigated the frequency of stem-like colonic cytotoxic T lymphocytes in each tissue source, representing various levels of inflammation and underlying illness. They defined extended clonotypes as those seen in more than one patient.

Researchers used the adoptive T lymphocyte transfer model of colitis to investigate the effect of stemness and T-follicular helper (TFH) gene expression on CD4+ T lymphocyte pathogenicity. They transferred naïve CD4⁺CD25^-5RB^high T lymphocytes to Rag^−/− mice and examined the pathogenicity of B-cell lymphoma 6 (BCL-6)-deficient helper T lymphocytes transplanted from BCL6^fl/flCre^CD4 mice to BCL6^fl/fl littermates.

They also investigated whether helper T lymphocytes in UC-active inflamed tissue may contribute to cytotoxic T lymphocyte pathogenesis. They performed single-cell transcriptome assays, T-cell receptor repertoire (TCR) analysis, single-cell trajectory analysis, gene set enrichment analysis (GSEA), and signature analysis to analyze human T lymphocytes.

Results

The study found colonic helper and cytotoxic T lymphocyte populations with genetic expression patterns similar to stem-type progenitor cells previously described in various rat models of infection, autoimmunity, allograft rejection, and malignancies. Stem-type T lymphocytes penetrated the intestinal tissue of UC patients.

Inflamed regions of UC patients contain higher amounts of stem-like cytotoxic T lymphocytes than non-inflamed areas, indicating that these cells can proliferate and self-renew in the presence of continuous antigenic stimulation. TCR sequencing analysis demonstrates that stem-type T lymphocytes are clonally linked to pro-inflammatory cytotoxic effector T lymphocyte populations, implying that they play a role in the maintenance of effectors that cause inflammation. Stem-like CD4+ lymphocytes are clonally related to T helper 17 (TH17) cells, indicating their role in UC pathogenesis.

The adoptive transfer UC mouse model demonstrated that helper T lymphocytes deficient in TCF1 or BCL-6, transcription factors promoting T lymphocyte stemness, had fewer colon T lymphocytes and were less harmful. BCL-6 loss decreased the pathogenicity of helper T lymphocytes, indicating that it may have impaired stemness function. TCF1 loss also lowered the pathogenicity of helper T lymphocytes.

The study found a link between stem-type T lymphocyte populations and ulcerative colitis pathogenesis, indicating that targeting this cellular population may improve clinical disease outcomes. T lymphocyte transcriptomes in UC patients' colon tissue showed cytotoxic and helper T lymphocyte populations in inflamed areas.

Stem-type T lymphocytes were clonally associated with pathogenic T lymphocyte populations, likely maintaining the survival of these effector cells, leading to chronic inflammation in UC patients' colons. The team also found elevated BCL-6 protein expression in UC-active inflammatory tissue.