The Role of T Cell Receptor Signaling in the Development of Type 1 Diabetes

Clark, Matthew; Kroger, Charles J.; Qin, Ke; Tisch, Roland

doi:10.3389/fimmu.2020.615371

Cited by 15 publications

(20 citation statements)

References 293 publications

(312 reference statements)

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“…We noticed that the signaling pathways associated with IL27 consisted of NLR signaling pathway, TLR signaling pathway, T cell receptor signaling pathway, RIG-I-like receptor signaling pathway, JAK-STAT signaling pathway, and apoptosis. Among them, the NLR signaling pathway (34), TLR signaling pathway (35), and T cell receptor signaling pathway (36,37) have been reported to be correlated with enhanced immune response, which is in line with our findings above. The RIG-I-like receptor signaling pathway is known to be implicated in apoptosis through the JAK-STAT signaling pathway (38,39), which seems to be contrary to enhanced immunity.…”

Section: Functional Annotation Of Il27supporting

confidence: 92%

Integrative Characterization of the Role of IL27 In Melanoma Using Bioinformatics Analysis

et al. 2021

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BackgroundIL27 has been reported to play dual roles in cancer; however, its effects on the tumor microenvironment (TME), immunotherapy, and prognosis in melanoma remain largely unclear. This study was aimed to uncover the effects of IL27 on TME, immunotherapy and prognosis in patients with melanoma.MethodsRNA-seq data, drug sensitivity data, and clinical data were obtained from TCGA, GEO, CCLE, and CTRP. Log-rank test was used to determine the survival value of IL27. Univariate and multivariate Cox regression analyses were employed to determine the independent predictors of survival outcomes. DAVID and GSEA were used to perform gene set functional annotations. ssGSEA was used to explore the association between IL27 and immune infiltrates. ConsensusClusterPlus was used to classify melanoma tissues into hot tumors or cold tumors.ResultsClinically, IL27 was negatively correlated with Breslow depth (P = 0.00042) and positively associated with response to radiotherapy (P = 0.038). High IL27 expression showed an improved survival outcome (P = 0.00016), and could serve as an independent predictor of survival outcomes (hazard ratio: 0.32 - 0.88, P = 0.015). Functionally, elevated IL27 expression could induce an enhanced immune response and pyroptosis (R = 0.64, P = 1.2e-55), autophagy (R = 0.37, P = 7.1e-17) and apoptosis (R = 0.47, P = 1.1e-27) in patients with melanoma. Mechanistically, elevated IL27 expression was positively correlated with cytotoxic cytokines (including INFG and GZMB), enhanced immune infiltrates, and elevated CD8/Treg ratio (R = 0.14, P = 0.02), possibly driving CD8+ T cell infiltration by suppressing β-catenin signaling in the TME. Furthermore, IL27 was significantly associated with hot tumor state, multiple predictors of response to immunotherapy, and improved drug response in patients with melanoma.ConclusionsIL27 was correlated with enriched CD8+ T cells, desirable therapeutic response and improved prognosis. It thus can be utilized as a promising modulator in the development of cytokine-based immunotherapy for melanoma.

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Section: Functional Annotation Of Il27supporting

confidence: 92%

Integrative Characterization of the Role of IL27 In Melanoma Using Bioinformatics Analysis

et al. 2021

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“…TCR activation promotes a number of signaling cascades that determine cell fate through regulating cytokine production, cell survival, proliferation, and differentiation. TCR signaling events drive the progression of T1DM by affecting T-cell development ( 33 ). Sequencing of TCR gene in pancreatic islets of T1DM donors reveals repeat clonal expansion and supports the existence of public TCRs shared among T1DM ( 34 – 37 ).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analyses of Type 1 Diabetes Ketosis- or Ketoacidosis-Related Genes in Activated CD56+CD16+ NK Cells

Shi

Dai

et al. 2021

Front. Endocrinol.

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ObjectivesAlterations in natural killer (NK) cells activity cause damage to pancreatic islets in type 1 diabetes mellitus (T1DM). The aim of this study is to identify T1DM ketosis- or ketoacidosis-related genes in activated CD56+CD16+ NK cells.MethodsMicroarray datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were analyzed using the GEO2R tool. Enrichment analyses were performed using Metascape online database and GSEA software. Cell-specific gene co-expression network was built using NetworkAnalyst tools. Cytoscape software was used to identify hub genes and construct co-expressed networks. Target miRNAs were predicted based on the DIANA-micro T, miRDB, and miRWalk online databases.ResultsA total of 70 DEGs were identified between T1DM patients recovered from ketosis or ketoacidosis and healthy control blood samples in GSE44314. Among the DEGs, 10 hub genes were screened out. The mature NK cell-specific gene co-expression network for DEGs in T1DM was built using NetworkAnalyst tools. DEGs between activated CD56+CD16+ NK cells and CD56brightCD16- NK cells were identified from GSE1511. After intersection, 13 overlapping genes between GSE44314 and GSE1511 microarray datasets were screened out, in which 7 hub genes were identified. Additionally, 59 target miRNAs were predicted according to the 7 hub genes. After validating with the exosome miRNA expression profile dataset of GSE97123, seven differentially expressed miRNAs (DEmiRNAs) in plasma-derived exosome were selected. Finally, a mRNA–miRNA network was constructed, which was involved in the T1DM ketosis or ketoacidosis process.ConclusionThis work identified seven hub genes in activated CD56+CD16+ NK cells and seven miRNAs in plasma-derived exosome as potential predictors of T1DM ketoacidosis, which provided a novel insight for the pathogenesis at the transcriptome level.

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“…As discussed above, there are many advantages of single cell sequencing TCRs over bulk TCR repertoire sequencing. Before the advent of large scale scRNAseq, many people in the type 1 diabetes field appreciated the importance of sequencing immunoreceptors on a single cell basis and linking this to antigen specificity and affinity (40)(41)(42). As of 2017 there were 1655 clonotypes of known specificity for T1D autoantigens (41), a number which has increased substantially with the advent of higher throughput scRNAseq.…”

Section: Methods To Identify Antigen Specific T Cellsmentioning

confidence: 99%

Insights From Single Cell RNA Sequencing Into the Immunology of Type 1 Diabetes- Cell Phenotypes and Antigen Specificity

et al. 2021

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In the past few years, huge advances have been made in techniques to analyse cells at an individual level using RNA sequencing, and many of these have precipitated exciting discoveries in the immunology of type 1 diabetes (T1D). This review will cover the first papers to use scRNAseq to characterise human lymphocyte phenotypes in T1D in the peripheral blood, pancreatic lymph nodes and islets. These have revealed specific genes such as IL-32 that are differentially expressed in islet –specific T cells in T1D. scRNAseq has also revealed wider gene expression patterns that are involved in T1D and can predict its development even predating autoantibody production. Single cell sequencing of TCRs has revealed V genes and CDR3 motifs that are commonly used to target islet autoantigens, although truly public TCRs remain elusive. Little is known about BCR repertoires in T1D, but scRNAseq approaches have revealed that insulin binding BCRs commonly use specific J genes, share motifs between donors and frequently demonstrate poly-reactivity. This review will also summarise new developments in scRNAseq technology, the insights they have given into other diseases and how they could be leveraged to advance research in the type 1 diabetes field to identify novel biomarkers and targets for immunotherapy.

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The Role of T Cell Receptor Signaling in the Development of Type 1 Diabetes

Cited by 15 publications

References 293 publications

Integrative Characterization of the Role of IL27 In Melanoma Using Bioinformatics Analysis

Integrative Characterization of the Role of IL27 In Melanoma Using Bioinformatics Analysis

Comprehensive Analyses of Type 1 Diabetes Ketosis- or Ketoacidosis-Related Genes in Activated CD56+CD16+ NK Cells

Insights From Single Cell RNA Sequencing Into the Immunology of Type 1 Diabetes- Cell Phenotypes and Antigen Specificity

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