Dataset Information

A Population of CD4⁺CD8⁺ Double-Positive T Cells Associated with Risk of Plasma Leakage in Dengue Viral Infection.

ABSTRACT: According to the WHO 2009 classification, dengue with warning signs is at the risk of developing severe form of dengue disease. One of the most important warning signs is plasma leakage, which can be a serious complication associated with higher morbidity and mortality. We report that the frequency of CD4⁺CD8⁺ double-positive (DP) T cells is significantly increased in patients at risk of developing plasma leakage. Transcriptomic analysis demonstrated that CD4⁺CD8⁺ DP cells were distinct from CD4⁺ Single Positive (SP) T cells but co-clustered with CD8⁺ SP cells, indicating a largely similar transcriptional profile. Twenty significant differentially expressed (DE) genes were identified between CD4⁺CD8⁺ DP and CD8⁺ SP cells. These genes encode OX40 and CCR4 proteins as well as other molecules associated with cell signaling on the cell surface (NT5E, MXRA8, and PTPRK). While comparing the profile of gene expression in CD4⁺CD8⁺ DP cells from patients with and without warning signs of plasma leakage, similar expression profile was observed, implying a role of CD4⁺CD8⁺ DP cells in plasma leakage through a quantitative increase rather than functional alteration. This study provided novel insight into the host immune response during the acute febrile phase of DENV infection and the role of CD4⁺CD8⁺ DP T cells in the pathogenesis of plasma leakage.

SUBMITTER: Yu ED

PROVIDER: S-EPMC8779337 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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A Population of CD4+CD8+ Double-Positive T Cells Associated with Risk of Plasma Leakage in Dengue Viral Infection.

Yu Esther Dawen ED Wang Hao H da Silva Antunes Ricardo R Tian Yuan Y Tippalagama Rashmi R Alahakoon Shakila U SU Premawansa Gayani G Wijewickrama Ananda A Premawansa Sunil S De Silva Aruna Dharshan AD Frazier April A Grifoni Alba A Sette Alessandro A Weiskopf Daniela D

Viruses 20220105 1

According to the WHO 2009 classification, dengue with warning signs is at the risk of developing severe form of dengue disease. One of the most important warning signs is plasma leakage, which can be a serious complication associated with higher morbidity and mortality. We report that the frequency of CD4+CD8+ double-positive (DP) T cells is significantly increased in patients at risk of developing plasma leakage. Transcriptomic analysis demonstrated that CD4+CD8 ...[more]

PMID: 35062294

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Project description:Background and aimsUlcerative colitis (UC) is a heterogeneous disorder with complex pathogenesis. Therefore, in the present study, we aimed to assess genome-wide DNA methylation changes associated explicitly with the pathogenesis of UC.MethodsDNA methylation changes were identified by comparing UC tissues with healthy controls (HCs) from the GEO databases. The candidate genes were obtained and verified in clinical samples. Moreover, the underlying molecular mechanism related to Zbtb7b in the pathogenesis of UC was explored using the dextran sodium sulfate (DSS)-induced colitis model.ResultsBioinformatic analysis from GEO databases confirmed that Zbtb7b, known as Th-inducing POZ-Kruppel factor (ThPOK), was demethylated in UC tissues. Then, we demonstrated that Zbtb7b was in a hypo-methylation pattern through the DSS-induced colitis model (P = 0.0357), whereas the expression of Zbtb7b at the mRNA and protein levels was significantly up-regulated in the inflamed colonic tissues of UC patients (qRT-PCR, WB, IHC: P < 0.0001, P = 0.0079, P < 0.0001) and DSS-induced colitis model (qRT-PCR, WB, IHC: P < 0.0001, P = 0.0045, P = 0.0004). Moreover, the expression of Zbtb7b was positively associated with the degree of UC activity. Mechanically, over-expression of Zbtb7b might activate the maturation of CD4+T cells (FCM, IF: P = 0.0240, P = 0.0003) and repress the differentiation of double-positive CD4+CD8+T (DP CD4+CD8+T) cells (FCM, IF: P = 0.0247, P = 0.0118), contributing to the production of inflammatory cytokines, such as TNF-α (P = 0.0005, P = 0.0005), IL-17 (P = 0.0014, P = 0.0381), and IFN-γ (P = 0.0016, P = 0.0042), in the serum and colonic tissue of DSS-induced colitis model.ConclusionsEpigenetic DNA hypo-methylation of Zbtb7b activated the maturation of CD4+T cells and repressed the differentiation of DP CD4+CD8+ T cells, resulting in the production of inflammatory cytokines and colonic inflammation in UC. Therefore, Zbtb7b might be a diagnostic and therapeutic biomarker for UC, and hypo-methylation might affect the biological function of Zbtb7b.

Project description:BackgroundHigh-affinity tumor antigen-specific T-cell receptor (TCR) gene is required to engineer potent T cells for therapeutic treatment of cancer patients. However, discovery of suitable therapeutic TCR genes is hampered by the fact that naturally occurring tumor antigen-specific TCRs are generally of low-affinity, and artificial modification of TCRs can mediate cross-reactivity to other antigens expressed in normal tissues. Here, we discovered a naturally occurring T-cell clone which expressed high-affinity HLA-A*02:01 (A*02)-restricted TCR against NY-ESO-1 from a patient who had NY-ESO-1-expressing ovarian tumor.MethodsA*02-restricted NY-ESO-1-specific T-cell clones were established from peripheral blood of patients who had NY-ESO-1-expressing ovarian tumors. TCR α and β chain genes were retrovirally transduced into polyclonally activated T cells. Phenotype and function of the parental and TCR-transduced T cells were analyzed by flow cytometry, ELISA and cytotoxicity assay. In vivo therapeutic efficacy was investigated in a xenograft model using NOD/SCID/IL-2Rγ-deficient (NSG) mice.ResultsA rare population of NY-ESO-1-specific T cells, which we named 19305DP, expressed cell surface CD4, CD8α, and CD8β but not CD56 and recognized A*02+NY-ESO-1+ cancer cell lines in a CD4- and CD8-independent manner. 19305DP showed a gene expression profile that is consistent with a mixed profile of CD4+ and CD8+ single-positive T cells. Both CD4+ and CD8+ T cells that were retrovirally transduced with 19305DP-derived TCR gene (19305DP-TCR) showed strong reactivity against A*02+NY-ESO-1+ cancer cells, whereas TCR genes from the conventional A*02-restricted NY-ESO-1-specific CD8+ single-positive T-cell clones functioned only in CD8+ T cells. Both 19305DP-TCR gene-engineered CD4+ and CD8+ T cells eliminated A*02+NY-ESO-1+ tumor xenografts in NSG mice. Finally, based on reactivity against a series of alanine-substituted peptides and a panel of normal human tissue-derived primary cells, 19305DP-TCR was predicted to have no cross-reactivity against any human non-NY-ESO-1 proteins.ConclusionTogether, our results indicate that the naturally occurring 19305DP-TCR derived from CD4+CD8+ double-positive αβ T cells, is a promising therapeutic TCR gene for effective and safe adoptive T-cell therapy in A*02+ patients with NY-ESO-1-expressing tumor.

Dataset Information

A Population of CD4⁺CD8⁺ Double-Positive T Cells Associated with Risk of Plasma Leakage in Dengue Viral Infection.

Publications

A Population of CD4<sup>+</sup>CD8<sup>+</sup> Double-Positive T Cells Associated with Risk of Plasma Leakage in Dengue Viral Infection.

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