Single-Cell RNA Sequencing of Blood and Ileal T Cells From Patients With Crohn's Disease Reveals Tissue-Specific Characteristics and Drug Targets

Venema, Werna T. Uniken; Voskuil, Michiel; Vila, Arnau Vich; Vries, Gerben van der; Jansen, Bernadien H.; Jabrì, Bana; Faber, Klaas Nico; Dijkstra, Gerard; Xavier, Ramnik J.; Wijmenga, Cisca; Graham, Daniel B.; Weersma, Rinse K.; Festen, Eleonora A. M.

doi:10.1053/j.gastro.2018.10.046

Cited by 57 publications

(33 citation statements)

References 12 publications

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“…REG1 proteins are involved in cell differentiation and proliferation within the gastrointestinal tract [38,39], and have been implicated in intestinal inflammation. For example, they showed upregulation during intestinal inflammation in infectious colitis [40]; were found to be up-regulated in metaplastic Paneth cells in both un-inflamed and inflamed colonic mucosa from IBD patients, with increased expression during inflammation [41,42]; and REG1A/REG1B was also found to be widely expressed in a newly identified T-cell subtype isolated from CD patients using a single-cell analysis of intestinal T cells [43]. Finally, genes MUC1 and MUC4 encode membrane-bound mucins from epithelial cells which aid in the intestinal mucosal barrier function [44][45][46].…”

Section: Discussionmentioning

confidence: 99%

Molecular Changes in the Non-Inflamed Terminal Ileum of Patients with Ulcerative Colitis

Lee

Vancamelbeke

Verstockt

et al. 2020

Cells

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Ulcerative colitis is a chronic inflammatory disease confined to the colon. Although the etiopathogenesis remains unknown, small bowel dysfunctions like histological and permeability alterations have been described in ulcerative colitis. We evaluated the molecular gene signature in the non-inflamed terminal ileum of 36 ulcerative colitis patients (7 active, with Mayo endoscopic subscore ≥2, and 29 inactive) as compared to 15 non-inflammatory bowel disease controls. Differential gene expression analysis with DESeq2 showed distinct expression patterns depending on disease activity and maximal disease extent. We found 84 dysregulated genes in patients with active extensive colitis and 20 in inactive extensive colitis, compared to controls. There was an overlap of 5 genes: REG1B, REG1A, MUC4, GRAMD2, and CASP10. In patients with left-sided colitis, ileal gene expression levels were similar to controls. Based on gene co-expression analysis, ileal changes in active ulcerative colitis patients were related to immune functions. The ileal changes in the inactive ulcerative colitis subjects converged into the maintenance of the intestinal barrier through increased mitochondrial function and dampened immune functions. In conclusion, we identified molecular changes in the non-inflamed ileum of ulcerative colitis that are dependent on colonic inflammation.

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Section: Discussionmentioning

confidence: 99%

Molecular Changes in the Non-Inflamed Terminal Ileum of Patients with Ulcerative Colitis

Lee

Vancamelbeke

Verstockt

et al. 2020

Cells

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“…For example, scRNA‐seq of CD3 + T cells revealed that the quiescent T cells mainly distribute in peripheral blood, cytotoxic T lymphocytes are mainly from intraepithelial T lymphocytes (IELs), and Th17 cells dominate in lamina propria T lymphocytes (LPLs). Another interesting phenomenon is that more CD‐risk genes are enriched in IELs and LPLs than those in PBLs, suggesting IELs and LPLs play a major role in intestinal inflammation . Especially, Th17 is a subset of T cells that secrete IL‐17 and plays an important role in autoimmune diseases.…”

Section: Application Of Scrna‐seq In Immunologymentioning

confidence: 99%

Dissecting the human immune system with single cell RNA sequencing technology

Liu

et al. 2019

Journal of Leukocyte Biology

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Single‐cell RNA sequencing (scRNA‐seq) is a powerful new technology allowing the analysis of transcriptomes from individual cell and is ideally suited to dissect immune cell heterogeneity. ScRNA‐seq has already been applied to identify novel immune cell subsets, elaborate cellular differentiation trajectories, and elucidate immunopathogenic mechanisms. Here, we briefly discuss the recent progresses and challenges in the scRNA‐seq technology including the workflow, recent applications in immunology, and potential hurdles that need to be overcome. This review will highlight how single cell technology promotes our understanding of human immunology.

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“… 22 Recently, single-cell RNA-sequencing of ileal biopsies from patients with Crohn’s disease found upregulation of LAG-3 expression in the cytotoxic T lymphocytes of the intestinal mucosa. 23 …”

Section: Introductionmentioning

confidence: 99%

Lymphocyte Activation Gene (LAG)-3 Is Associated With Mucosal Inflammation and Disease Activity in Ulcerative Colitis

Slevin

Garner

Lahiff

et al. 2020

Journal of Crohn's and Colitis

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Background and Aims Lymphocyte activation gene [LAG]-3 is an immune checkpoint and its expression identifies recently activated lymphocytes that may contribute to inflammation. We investigated the role of LAG-3 by analysing its expression and function in immune cells from blood and tissue of patients with ulcerative colitis [UC]. Methods The phenotypic properties of LAG-3+ T cells were determined by flow cytometry, qRT-PCR and single-cell RNA-sequencing. LAG-3+ cells were quantified and correlated with disease activity. The functional effects of LAG-3+ cells were tested using a depleting anti-LAG-3 monoclonal antibody [mAb] in a mixed lymphocyte reaction [MLR]. Results LAG-3+ cells in the blood were negligible. LAG-3+ lymphocytes were markedly increased in inflamed mucosal tissue and both frequencies of LAG-3+ T cells and transcript levels of LAG3 correlated with endoscopic severity. LAG-3 expression was predominantly on effector memory T cells, and single-cell RNA-sequencing revealed LAG3 expression in activated and cytokine-producing T cell subsets. Foxp3+CD25hi Tregs also expressed LAG-3, although most mucosal Tregs were LAG-3−. Mucosal LAG-3+ cells produced mainly interferon γ [IFNγ] and interleukin-17A. LAG-3+ cell numbers decreased in patients who responded to biologics, and remained elevated in non-responders. Treatment with a depleting anti-LAG-3 mAb led to a reduction in proliferation and IFNγ production in an MLR. Conclusions LAG-3+ cells are increased in the inflamed mucosa, predominantly on effector memory T cells with an activated phenotype and their cell numbers positively correlate with disease activity. Depleting LAG-3 eliminates activated proliferating T cells, and hence LAG-3 could be a therapeutic target in UC.

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Single-Cell RNA Sequencing of Blood and Ileal T Cells From Patients With Crohn's Disease Reveals Tissue-Specific Characteristics and Drug Targets

Cited by 57 publications

References 12 publications

Molecular Changes in the Non-Inflamed Terminal Ileum of Patients with Ulcerative Colitis

Molecular Changes in the Non-Inflamed Terminal Ileum of Patients with Ulcerative Colitis

Dissecting the human immune system with single cell RNA sequencing technology

Lymphocyte Activation Gene (LAG)-3 Is Associated With Mucosal Inflammation and Disease Activity in Ulcerative Colitis

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