Gene Microarrays Reveal Extensive Differential Gene Expression in Both CD4+ and CD8+ Type 1 and Type 2 T Cells

Chtanova, Tatyana; Kemp, Roslyn A.; Sutherland, Andrew P. R.; Ronchese, Franca; Mackay, Charles R.

doi:10.4049/jimmunol.167.6.3057

Cited by 122 publications

(91 citation statements)

References 50 publications

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“…After 48 h, the effects of IL-12 were clear and altogether 41 genes became regulated by IL-12 (Table II). Among these were only a few genes, such as SOCS3, CEBPB, and IL-7R that have a previously described role in Th1 and Th2 cell responses (13,19,20). Most of the genes regulated by IL-12 were also regulated by IL-4 and/or activation alone (Fig.…”

Section: The Slow Response To Il-12mentioning

confidence: 84%

“…We have conducted a genome-wide screening to identify novel genes involved in early Th1 and Th2 differentiation (13,15). Interestingly, numerous factors with known or unknown function were identified to be implicated in the process.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, an increasing number of studies have used DNA microarrays to identify new factors involved in the Th1 and Th2 polarization in humans and mice (7)(8)(9)(10)(11)(12)(13)(14). However, all of these studies have focused on studying a limited number of primarily known genes.…”

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confidence: 99%

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Genome-Wide Identification of Novel Genes Involved in Early Th1 and Th2 Cell Differentiation

Lund

Löytömäki

Naumanen

et al. 2007

The Journal of Immunology

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Th cell subtypes, Th1 and Th2, are involved in the pathogenesis or progression of many immune-mediated diseases, such as type 1 diabetes and asthma, respectively. Defining the molecular networks and factors that direct Th1 and Th2 cell differentiation will help to understand the pathogenic mechanisms causing these diseases. Some of the key factors regulating this differentiation have been identified, however, they alone do not explain the process in detail. To identify novel factors directing the early differentiation, we have studied the transcriptomes of human Th1 and Th2 cells after 2, 6, and 48 h of polarization at the genome scale. Based on our current and previous studies, 288 genes or expressed sequence tags, representing ∼1–1.5% of the human genome, are regulated in the process during the first 2 days. These transcriptional profiles revealed genes coding for components of certain pathways, such as RAS oncogene family and G protein-coupled receptor signaling, to be differentially regulated during the early Th1 and Th2 cell differentiation. Importantly, numerous novel genes with unknown functions were identified. By using short-hairpin RNA knockdown, we show that a subset of these genes is regulated by IL-4 through STAT6 signaling. Furthermore, we demonstrate that one of the IL-4 regulated genes, NDFIP2, promotes IFN-γ production by the polarized human Th1 lymphocytes. Among the novel genes identified, there may be many factors that play a crucial role in the regulation of the differentiation process together with the previously known factors and are potential targets for developing therapeutics to modulate Th1 and Th2 responses.

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Section: The Slow Response To Il-12mentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

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Genome-Wide Identification of Novel Genes Involved in Early Th1 and Th2 Cell Differentiation

Lund

Löytömäki

Naumanen

et al. 2007

The Journal of Immunology

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“…This latter issue also bears on the failure of gene array studies comparing Th1 and Th2 cells to note a difference in CD4 mRNA levels in these two cell types that would account for the data reported here. The surface difference we see is only twofold, which many array analyses use as a cut-off [23,24]. Some have suggested that IL-4 is a "dangerous" cytokine and that the pseudo-monoallelic nature of IL-4 gene expression is a mechanism evolved to limit production of this potentially harmful molecule [25].…”

Section: Discussionmentioning

confidence: 99%

Decreased CD4 expression by polarized T helper 2 cells contributes to suboptimal TCR-induced phosphorylation and reduced Ca2+ signaling

et al. 2005

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Polarized Th1 and Th2 cells expressing the same TCR produce distinct biochemical responses to ligand engagement. Compared to Th1 cells, Th2 cells show altered substrate tyrosine phosphorylation and a diminished or transient Ca 2+ response. Here we demonstrate that agonist stimulation of Th1 cells leads to the predominant appearance of fully phosphorylated (p23) TCR f, substantial phosphorylation of zetaassociated protein 70 (ZAP-70), and strong elevation of intracellular Ca 2+ , whereas agonist stimulation of Th2 cells expressing an identical TCR results in an elevated p21:p23 TCR f ratio, little or no detectable ZAP-70 phosphorylation, and a more limited elevation in intracellular Ca 2+ . Th2 cells consistently had twofold lower surface CD4 expression as compared to Th1 cells with the same TCR. When CD4 levels in Th2 cells were raised to Th1 levels using retroviral gene transfer, the transduced cells showed greater generation of p23 phospho-f, measurable phosphorylation of ZAP-70, and increased Ca 2+ responses. These findings suggest that the apparent qualitative differences in TCR signaling characterizing Th1 versus Th2 cells are largely the result of modest quantitative variation in CD4 expression, with decreased CD4 expression playing a significant role in attenuating the proximal signaling responsiveness of Th2 cells to TCR ligands.Supporting information for this article is available at http://www.wileyvch.de/contents/jc_2040/2005/26064_s.pdf IntroductionWhile it is an oversimplification of in vivo physiology, the Th1-Th2 model is a convenient and generally applicable paradigm for naive CD4 + T cell differentiation [1,2]. The set of effector cytokines produced by an antigenactivated CD4 + T cell is largely determined by the particular combination of T cell receptor (TCR), cytokine, and costimulatory signals received by the naive T cell. In particular, T cells expressing the same The altered downstream phosphorylation seen in Th2 cells resembles that reported by this laboratory for Th1 cells in which CD4-MHC class II interactions are disrupted [14]. Therefore, we undertook a re-examination of the status of the CD4 molecule in polarized Th2 cells. Here we report that such cells consistently show a lower surface level of CD4 expression than Th1 cells derived from the same precursor pool. This lower CD4 expression could be linked to the altered signaling pattern of the Th2 cells through experiments showing a switch to a more Th1-like pattern of tyrosine phosphorylation and Ca 2+ signaling following enhancement of CD4 expression using a retroviral vector. These data provide evidence that a modest quantitative change in expression of a surface receptor can have qualitative effects on signaling in differentiated T cells and that decreased CD4 expression plays a significant role in controlling the antigen responsiveness of polarized Th2 cells. Results Differential TCR down-modulation in response to agonist by Th1 vs. Th2 cells expressing identical TCRTo examine in a controlled fashion the origin of the differences...

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“…Microarray experiments have been carried out on various immune cell subsets by a number of different investigators in order to understand gene expression differences during differentiation and activation. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] These studies have provided invaluable insight into comprehensive gene expression profiles that define many different immune cell subsets and states of differentiation and activation. In particular, a recent study detailed elegantly the genes expressed specifically in many subsets of the T-cell lineage.…”

Section: Introductionmentioning

confidence: 99%

Immune response in silico (IRIS): immune-specific genes identified from a compendium of microarray expression data

Abbas¹,

Baldwin²,

Ma³

et al. 2005

Genes Immun

364

356

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Immune cell-specific expression is one indication of the importance of a gene's role in the immune response. We have compiled a compendium of microarray expression data for virtually all human genes from six key immune cell types and their activated and differentiated states. Immune Response In Silico (IRIS) is a collection of genes that have been selected for specific expression in immune cells. The expression pattern of IRIS genes recapitulates the phylogeny of immune cells in terms of the lineages of their differentiation. Gene Ontology assignments for IRIS genes reveal significant involvement in inflammation and immunity. Genes encoding CD antigens, cytokines, integrins and many other gene families playing key roles in the immune response are highly represented. IRIS also includes proteins of unknown function and expressed sequence tags that may not represent genes. The predicted cellular localization of IRIS proteins is evenly distributed between cell surface and intracellular compartments, indicating that immune specificity is important at many points in the signaling pathways of the immune response. IRIS provides a resource for further investigation into the function of the immune system and immune diseases.

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Gene Microarrays Reveal Extensive Differential Gene Expression in Both CD4+ and CD8+ Type 1 and Type 2 T Cells

Cited by 122 publications

References 50 publications

Genome-Wide Identification of Novel Genes Involved in Early Th1 and Th2 Cell Differentiation

Genome-Wide Identification of Novel Genes Involved in Early Th1 and Th2 Cell Differentiation

Decreased CD4 expression by polarized T helper 2 cells contributes to suboptimal TCR-induced phosphorylation and reduced Ca2+ signaling

Immune response in silico (IRIS): immune-specific genes identified from a compendium of microarray expression data

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