New Insights on CD8+ T Cells in Inflammatory Bowel Disease and Therapeutic Approaches

Casalegno-Garduño, Rosaely; Däbritz, Jan

doi:10.3389/fimmu.2021.738762

Cited by 61 publications

(42 citation statements)

References 113 publications

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“…The functions of CD8+T cells in IBD were reported controversial, with some reports indicating anti-colitogenic properties and others showing their contribution to tissue inflammation, which could be explained by the diversity of sources and subtypes ( 78 ).The best known CD8+ T cells, also called cytotoxic T lymphocytes (CTL), are characterized by robust production of IFN-γ and cytolytic activities ( 79 ). The increase of activated CTLs was observed both in peripheral blood and the affected intestinal mucosa ( 80 , 81 ).…”

Section: Discussionmentioning

confidence: 99%

Immune cells and their related genes provide a new perspective on the common pathogenesis of ankylosing spondylitis and inflammatory bowel diseases

2023

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BackgroundThe close relationship between ankylosing spondylitis (AS) and inflammatory bowel diseases (IBD) has been supported by many aspects, including but not limited to clinical manifestations, epidemiology and pathogenesis. Some evidence suggests that immune cells actively participated in the pathogenesis of both diseases. However, information on which cells are primarily involved in this process and how these cells mobilize, migrate and interact is still limited.MethodsDatasets were downloaded from Gene Expression Omnibus (GEO) database. Common differentially expressed genes (coDEGs) were identified by package “limma”. The protein-protein interaction (PPI) network and Weighted Gene Co-Expression Network Analysis (WGCNA) were used to analyze the interactions between coDEGs. KEGG pathway enrichment analysis and inverse cumulative distribution function were applied to identify common differential pathways, while Gene Set Enrichment Analysis (GSEA) was used to confirm the significance. Correlation analysis between coDEGs and immune cells led to the identification of critical immune-cell-related coDEGs. The diagnostic models were established based on least absolute shrinkage and selection operator (LASSO) regression, while receiver operating characteristic (ROC) analysis was used to identify the ability of the model. Validation datasets were imported to demonstrate the significant association of coDEGs with specific immune cells and the capabilities of the diagnostic model.ResultsIn total, 67 genes were up-regulated and 185 genes were down-regulated in both diseases. Four down-regulated pathways and four up-regulated pathways were considered important. Up-regulated coDEGs were firmly associated with neutrophils, while down-regulated genes were significantly associated with CD8+ T−cells and CD4+ T−cells in both AS and IBD datasets. Five up-regulated and six down-regulated key immue-cell-related coDEGs were identified. Diagnostic models based on key immue-cell-related coDEGs were established and tested. Validation datasets confirmed the significance of the correlation between coDEGs and specific immune cells.ConclusionThis study provides fresh insights into the co-pathogenesis of AS and IBD. It is proposed that neutrophils and T cells may be actively involved in this process, however, in opposite ways. The immue-cell-related coDEGs, revealed in this study, may be relevant to their regulation, although relevant research is still lacking.

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Section: Discussionmentioning

confidence: 99%

Immune cells and their related genes provide a new perspective on the common pathogenesis of ankylosing spondylitis and inflammatory bowel diseases

2023

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“…The primary site of inflammation in IBD is the intestine, where the mucosal barrier should be maintained to control pathogens while being tolerant towards commensals. Integrity loss of this single layer of epithelial cells leads to entry of luminal content into LP and a subsequent inflammatory immune response by tissue-resident and immigrant immune cells, decisively driven by T cells (22, 23). Therefore, we analyzed CD3 + T cells within IELs and LPLs as well as PBMCs by mass cytometry / CyTOF.…”

Section: Discussionmentioning

confidence: 99%

“…Blood from CD patients and HD were collected in NH4-Heparin tubes (Sarstedt). The median age of healthy donors is 37 (22–67) years and the median age of CD patients is 39 (23–62) years. Both groups contain males (59%) and females (41%).…”

Section: Methodsmentioning

confidence: 99%

“…Broad immune cell phenotyping of PBMCs vs. tissues of IBD patients has been performed (19–21). Since CD3 + T cells, both CD4 + and CD8 + , are thought to be key players in CD (22, 23), we here aimed to perform a deep immune characterization using mass cytometry (Cytometry by Time-of-Flight, CyTOF) together with manual and computation data analysis, and offer a detailed description of CD3 + T-cell heterogeneity in a CD context. Moreover, to relate subtypes stringently to areas of inflammation, we further discriminated between inflamed and not inflamed lamina propria (LP) as well as epithelium of the same CD patient, additionally analyzing their blood in comparison to matched healthy donors (HD) (Figure 1A).…”

Section: Introductionmentioning

confidence: 99%

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Pro-inflammatory innate-like T cells are expanded in the blood and inflamed intestine in Crohn’s Disease

Chiarolla

Schulz

Meir

et al. 2022

Preprint

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A complex and tissue-specific network of cells including T lymphocytes maintains intestinal homeostasis. To address disease and tissue-specific alterations, we performed a T cell-centric mass cytometry analysis of peripheral and intestinal lymphocytes from patients with Crohn’s disease (CD) and healthy donor PBMCs. We compared inflamed and not inflamed tissue areas of bowel resections. Chronic inflammation enforced activation, exhaustion and terminal differentiation of CD4+ and CD8+ T cells and an enrichment of CD4+Foxp3+ cells (Tregs) in inflamed intestine. However, tissue-repairing Tregs decreased, while enigmatic rare Foxp3+ T-cell subsets appeared upon inflammation. In vitro assays revealed that those subsets, e.g. CD4+Foxp3+HLA-DR+TIGIT− and CD4+Foxp3+CD56+, express pro-inflammatory IFN-γ. Some T-conventional (Tcon) cells tended towards innateness. In blood of CD patients, not well studied CD4+ and CD8+ subsets of CD16+CCR6+CD127+ T cells appeared anew, a phenotype reproducible by incubation of healthy blood T cells with patient blood plasma. Together, these findings suggest a bias towards innate-like pro-inflammatory Tregs and innate-like Tcon, which act with less specific cytotoxicity. Most likely, this is both cause and consequence of intestinal inflammation during CD.Graphical Abstract

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“…7,8,10 Besides clinical overlaps with CC, LC shares features with IBDs ulcerative colitis (UC) and Crohn's disease (CD) such as Th1/Th17-driven immune responses, tight-junction claudin dysregulation, and water channel aquaporin downregulation. [11][12][13][14][15][16][17][18][19] Interestingly, incidence of CD and UC increases in patients previously diagnosed of LC and CC. 6,20,21 Indeed, both LC and CC have been suggested to be attenuated IBD forms where an overt mucosal inflammation remains restrained.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic profiling of lymphocytic colitis highlights distinct diarrhoeal pathomechanisms

Bhardwaj

Münch

Montague

et al. 2023

Preprint

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Background and Aims: The pathobiology of the non-destructive inflammatory bowel disease (IBD) lymphocytic colitis (LC) is poorly understood. Our aim was to define a LC-specific transcriptome to gain insight into LC pathology, identify genetic signatures uniquely linked to LC, and uncover potentially druggable disease pathways. Methods: We performed whole mucosa bulk RNA-sequencing of LC and CC samples from patients with active disease, and healthy controls (n=4-10 per cohort). Differential gene expression was analyzed by gene-set enrichment and deconvolution analyses to identify pathologically relevant pathways and cells, respectively, altered in LC. Key findings were validated using reverse transcription quantitative PCR and/or immunohistochemistry. Finally, we compared our sequencing data to a previous cohort of ulcerative colitis and Crohn's disease patients (n=4 per group) to distinguish non-destructive from classic IBD. Results: The LC-specific transcriptome was defined by a limited mucosal immune response against microbiota compared to CC and classic IBD samples. In contrast, we noted a distinct induction of regulatory non-coding RNA species in LC samples. Moreover, compared to CC, we observed decreased water channel and cell adhesion molecule gene expression, which was associated with reduced intestinal epithelial cell proliferation. Conclusions: We conclude that LC is a pathomechanistically distinct disease that is characterized by a dampened immune response despite massive mucosal immune cell infiltration. Our results point to regulatory micro-RNAs as a potential disease-specific feature that may be amenable to therapeutic intervention.

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New Insights on CD8+ T Cells in Inflammatory Bowel Disease and Therapeutic Approaches

Cited by 61 publications

References 113 publications

Immune cells and their related genes provide a new perspective on the common pathogenesis of ankylosing spondylitis and inflammatory bowel diseases

Immune cells and their related genes provide a new perspective on the common pathogenesis of ankylosing spondylitis and inflammatory bowel diseases

Pro-inflammatory innate-like T cells are expanded in the blood and inflamed intestine in Crohn’s Disease

Transcriptomic profiling of lymphocytic colitis highlights distinct diarrhoeal pathomechanisms

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