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Cytokine diversity in the Th1-dominated human anti-influenza response caused by variable cytokine expression by Th1 cells, and a minor population of uncommitted IL-2+IFN?- Thpp cells.

ABSTRACT: Within overall Th1-like human memory T cell responses, individual T cells may express only some of the characteristic Th1 cytokines when reactivated. In the Th1-oriented memory response to influenza, we have tested the contributions of two potential mechanisms for this diversity: variable expression of cytokines by a uniform population during activation, or different stable subsets that consistently expressed subsets of the Th1 cytokine pattern. To test for short-term variability, in vitro-stimulated influenza-specific human memory CD4+ T cells were sorted according to IL-2 and IFN? expression, cultured briefly in vitro, and cytokine patterns measured after restimulation. Cells that were initially IFN?+ and either IL-2+ or IL-2- converged rapidly, containing similar proportions of IL-2-IFN?+ and IL-2+IFN?+ cells after culture and restimulation. Both phenotypes expressed Tbet, and similar patterns of mRNA. Thus variability of IL-2 expression in IFN?+ cells appeared to be regulated more by short-term variability than by stable differentiated subsets. In contrast, heterogeneous expression of IFN? in IL-2+ influenza-specific T cells appeared to be due partly to stable T cell subsets. After sorting, culture and restimulation, influenza-specific IL-2+IFN?- and IL-2+IFN?+ cells maintained significantly biased ratios of IFN?+ and IFN?- cells. IL-2+IFN?- cells included both Tbetlo and Tbethi cells, and showed more mRNA expression differences with either of the IFN?+ populations. To test whether IL-2+IFN?-Tbetlo cells were Thpp cells (primed but uncommitted memory cells, predominant in responses to protein vaccines), influenza-specific IL-2+IFN?- and IL-2+IFN?+ T cells were sorted and cultured in Th1- or Th2-generating conditions. Both cell types yielded IFN?-secreting cells in Th1 conditions, but only IL-2+IFN?- cells were able to differentiate into IL-4-producing cells. Thus expression of IL-2 in the anti-influenza response may be regulated mainly by short term variability, whereas different T cell subsets, Th1 and Thpp, may contribute to variability in IFN? expression.

SUBMITTER: Deng N

PROVIDER: S-EPMC4006810 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Cytokine diversity in the Th1-dominated human anti-influenza response caused by variable cytokine expression by Th1 cells, and a minor population of uncommitted IL-2+IFNγ- Thpp cells.

Deng Nan N Weaver Jason M JM Mosmann Tim R TR

PloS one 20140501 5

Within overall Th1-like human memory T cell responses, individual T cells may express only some of the characteristic Th1 cytokines when reactivated. In the Th1-oriented memory response to influenza, we have tested the contributions of two potential mechanisms for this diversity: variable expression of cytokines by a uniform population during activation, or different stable subsets that consistently expressed subsets of the Th1 cytokine pattern. To test for short-term variability, in vitro-stimu ...[more]

PMID: 24788814

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Project description:ObjectiveCancer immunotherapy has made remarkable advances in recent years, but its effectiveness in treating gastric cancer is often limited by the complexity of the tumor microenvironment and the lack of effective biomarkers. This study aimed to identify effective biomarkers for immunotherapy treatment by characterizing the tumor microenvironment.MethodsWe retrieved the RNA-seq data from gastric cancer patients treated with the programmed death 1 (PD-1) blockade pembrolizumab. Differentially expressed genes associated with clinical outcomes were identified and further analyzed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Gene signature scores were calculated by single sample Gene Set Enrichment Analysis (ssGSEA). The infiltration levels of immune cells were quantified using the xCell website. Cell type enrichment analysis was performed to compare treatment response and non-response groups, and regression analysis was used to investigate the relationship between interferon gamma (IFNγ) immune response and immune cell infiltration. Biomarkers were identified using least absolute shrinkage and selection operator (LASSO) analysis.ResultsCompared to normal tissues, cytokine activity and interleukin-6 production were highly activated in gastric tumors. Responders to pembrolizumab showed significantly up-regulated expression of IFNγ response-related genes. Cell type enrichment analysis revealed that Th1 cells were significantly enriched in the tumor microenvironment of responders. Regression analysis indicated that Th1 cells induced IFNγ response more efficiently than other cell types. Using signatures of Th1 cells, stromal cells and IFNγ response, a set of eight genes were identified that effectively predicted the efficacy of immunotherapy treatment and patient prognosis.ConclusionsTh1 cells promote therapeutic efficacy of PD-1 blockade by promoting IFNγ immune response in gastric cancer. The identified biomarkers have the potential to improve the effectiveness of immunotherapy treatment for gastric cancer patients.

Dataset Information

Cytokine diversity in the Th1-dominated human anti-influenza response caused by variable cytokine expression by Th1 cells, and a minor population of uncommitted IL-2+IFN?- Thpp cells.

Publications

Cytokine diversity in the Th1-dominated human anti-influenza response caused by variable cytokine expression by Th1 cells, and a minor population of uncommitted IL-2+IFNγ- Thpp cells.

Similar Datasets

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