Suppressive and Gut-Reparative Functions of Human Type 1 T Regulatory Cells

Cook, Laura; Ståhl, Martin; Han, Xiao; Nazli, Aisha; MacDonald, Katherine N.; Wong, May Q.; Tsai, Kevin; Dizzell, Sara; Jacobson, Kevan; Bressler, Brian; Kaushic, Charu; Vallance, Bruce A.; Steiner, Theodore S.; Levings, Megan K.

doi:10.1053/j.gastro.2019.09.002

Cited by 84 publications

(57 citation statements)

References 43 publications

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“…However, a previous study reported an increased percentage of Tregs as part of CD diagnosis, as well as during the active phase of the disease (Smids et al, 2018). Tregs generally suppress IL-1B production and inhibit effector T cell proliferation, whereas some studies reported that these function are impaired in CD (Maloy and Powrie, 2011;Cook et al, 2019). This suggests that Treg status in CD remains controversial and might depend on inflammatory stage.…”

Section: Discussionmentioning

confidence: 98%

Identification of Immune Cell Landscape and Construction of a Novel Diagnostic Nomogram for Crohn’s Disease

Chen

Yuan

et al. 2020

Front. Genet.

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Crohn's disease (CD) has an increasing incidence and prevalence worldwide. The etiology of CD remains unclear and there is no gold standard for diagnosis. The dysregulated immune response and different infiltration status of immune cells are critical for CD pathogenesis; therefore, it is important to provide an overview of immunecell alterations in CD and explore a novel method for auxiliary diagnosis. Here we analyzed microarray datasets from Gene Expression Omnibus (GEO), and an extended version of Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORTx) was utilized to estimate the fraction of 22 types of immune cells. Differentially expressed genes (DEGs) and a protein-protein interaction (PPI) network were identified, and we performed gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) to identify differentially regulated pathways in CD. Least absolute shrinkage and selection operator (LASSO) regression was conducted to filter features, and a diagnostic nomogram based on logistic regression was built and validated in an independent validation cohort. In the derivation cohort, we found a proportion of 17 immune-cell types to be significantly altered between CD and healthy controls and a total of 150 DEGs were identified, which were mostly related to the immune response. Among the 15 hub genes based on the PPI network, C-X-C chemokine ligand 8 (CXCL8) and interleukin-1B (IL-1B) showed the highest degree of interaction. Additionally, GSEA and GSVA identified five significantly enriched pathways, among which the nucleotide-binding oligomerization domain (NOD)-like receptor signaling pathway was critical in the CD development. Furthermore, six variables comprising of CXCL8, IL-1B, M1 macrophages, regulatory T cells, CD8 + T cells, and plasma cells were identified by LASSO regression and incorporated into a logistic regression model. The nomogram displayed a good prediction, with a 0.915 area under the receiver operating curve (AUC) and a C-index of 0.915 [95% confidence interval (CI): 0.875-0.955]. Similar results were found in the validation cohort, with an AUC of 0.884 and a 0.884 C-index (95% CI: 0.843-0.924). These results provide novel in silico insight into cellular and molecular characteristics of CD and potential biomarkers for diagnosis and targeted therapy.

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Section: Discussionmentioning

confidence: 98%

Identification of Immune Cell Landscape and Construction of a Novel Diagnostic Nomogram for Crohn’s Disease

Chen

Yuan

et al. 2020

Front. Genet.

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“…In peripheral blood of CD and UC patients circulating Tr1 frequencies may not differ from those of healthy individuals. Moreover, when isolated the cells have a similar phenotype and cytokine profile [248]. However, human intestinal IFN-γ-producing Tr1 cells co-expressing CCR5 and PD1 were found to down-regulate IL-10 in patients with IBD [249].…”

Section: The Role Of Tr1 Cells In Ibdmentioning

confidence: 93%

“…In a Phase I/II clinical trial with refractory CD, infusion of ovalbumin-specific Tr1 cell clones was tolerated and showed dose-dependent efficacy in patients suffering from severe disease suggesting the approach may have potential [255,256]. In particular, as functionally suppressive Tr1 cells can be isolated from the peripheral blood of IBD patients and expanded in vitro autologous Tr1 cells transfer could be a therapeutic option [248].…”

Section: Does Adoptive Transfer Of Tr1 Cells Attenuate Disease?mentioning

confidence: 99%

Dissecting the Heterogeneity in T-Cell Mediated Inflammation in IBD

Tindemans

Joosse

Samsom

2020

Cells

110

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Infiltration of the lamina propria by inflammatory CD4+ T-cell populations is a key characteristic of chronic intestinal inflammation. Memory-phenotype CD4+ T-cell frequencies are increased in inflamed intestinal tissue of IBD patients compared to tissue of healthy controls and are associated with disease flares and a more complicated disease course. Therefore, a tightly controlled balance between regulatory and inflammatory CD4+ T-cell populations is crucial to prevent uncontrolled CD4+ T-cell responses and subsequent intestinal tissue damage. While at steady state, T-cells display mainly a regulatory phenotype, increased in Th1, Th2, Th9, Th17, and Th17.1 responses, and reduced Treg and Tr1 responses have all been suggested to play a role in IBD pathophysiology. However, it is highly unlikely that all these responses are altered in each individual patient. With the rapidly expanding plethora of therapeutic options to inhibit inflammatory T-cell responses and stimulate regulatory T-cell responses, a crucial need is emerging for a robust set of immunological assays to predict and monitor therapeutic success at an individual level. Consequently, it is crucial to differentiate dominant inflammatory and regulatory CD4+ T helper responses in patients and relate these to disease course and therapy response. In this review, we provide an overview of how intestinal CD4+ T-cell responses arise, discuss the main phenotypes of CD4+ T helper responses, and review how they are implicated in IBD.

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“…In a similar manner, hybrid culture organoids with immune cells has allowed for ex vivo modelling of immuno-epithelial interactions, which include the cross-talk between leukocytes and organoids [102][103][104][105] , cytotoxicity of chimeric antigen-engineered lymphocytes 106 and tumour education of circulating T cells by co-culture with autologous tumour organoids 107 (Fig. 5b).…”

Section: Organoid Reverse Engineering For Genetic Disease Modellingmentioning

confidence: 99%

Somatic cell-derived organoids as prototypes of human epithelial tissues and diseases

2020

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Suppressive and Gut-Reparative Functions of Human Type 1 T Regulatory Cells

Abstract: BASIC AND TRANSLATIONAL AT might be developed as a cell-based therapy for intestinal inflammatory disorders.

Cited by 84 publications

References 43 publications

Identification of Immune Cell Landscape and Construction of a Novel Diagnostic Nomogram for Crohn’s Disease

Identification of Immune Cell Landscape and Construction of a Novel Diagnostic Nomogram for Crohn’s Disease

Dissecting the Heterogeneity in T-Cell Mediated Inflammation in IBD

Somatic cell-derived organoids as prototypes of human epithelial tissues and diseases

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