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Gene expression changes in long-term culture of T-cell clones: genomic effects of chronic antigenic stress in aging and immunosenescence.

Mazzatti DJ, White A, Forsey RJ, Powell JR, Pawelec G - Aging Cell (2007)

Bottom Line: Differentially expressed genes were confirmed by real-time polymerase chain reaction, and relationships between these assessed using Ingenuity Systems evidence-based association analysis.These pathways and affected genes may play a significant role in driving the cellular senescent phenotype and warrant further investigation as potential biomarkers of aging and senescence.These genes may additionally provide targets for intervention.

View Article: PubMed Central - PubMed

Affiliation: Unilever Corporate Research, Colworth Park, Sharnbrook, Bedford MK44 1LQ, UK. dawn.mazzatti@unilever.com

ABSTRACT
The adaptive immune response requires waves of T-cell clonal expansion on contact with altered self and contraction after elimination of antigen. In the case of persisting antigen, as occurs for example in cytomegalovirus or Epstein-Barr virus infection, this critical process can become dysregulated and responding T-cells enter into a dysfunctional senescent state. Longitudinal studies suggest that the presence of increased numbers of such T-cells is a poor prognostic factor for survival in the very elderly. Understanding the nature of the defects in these T-cells might facilitate intervention to improve immunity in the elderly. The process of clonal expansion under chronic antigenic stress can be modelled in vitro using continuously cultured T-cells. Here, we have used cDNA array technology to investigate differences in gene expression in a set of five different T-cell clones at early, middle and late passage in culture. Differentially expressed genes were confirmed by real-time polymerase chain reaction, and relationships between these assessed using Ingenuity Systems evidence-based association analysis. Several genes and chemokines related to induction of apoptosis and signal transduction pathways regulated by transforming growth factor beta (TGFbeta), epidermal growth factor (EGF), fos and beta-catenin were altered in late compared to early passage cells. These pathways and affected genes may play a significant role in driving the cellular senescent phenotype and warrant further investigation as potential biomarkers of aging and senescence. These genes may additionally provide targets for intervention.

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Related in: MedlinePlus

Network of genes differentially expressed in T-cell clone (TCC) immunosenescence. Forty-three genes that were differentially regulated in late passage, senescent, TCCs were analysed by the Ingenuity Pathway Analysis (IPA) tool. The network shown was significantly associated with cellular movement, haematological system development and function, immune response, cell-to-cell signaling and interaction, and cellular growth and proliferation (P < 0.01). Shaded genes were identified by microarray analysis as differentially expressed in TCC senescence. Other nodal genes are directly or indirectly associated with the differentially expressed genes. The meaning of the nodal shapes is indicated.
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fig01: Network of genes differentially expressed in T-cell clone (TCC) immunosenescence. Forty-three genes that were differentially regulated in late passage, senescent, TCCs were analysed by the Ingenuity Pathway Analysis (IPA) tool. The network shown was significantly associated with cellular movement, haematological system development and function, immune response, cell-to-cell signaling and interaction, and cellular growth and proliferation (P < 0.01). Shaded genes were identified by microarray analysis as differentially expressed in TCC senescence. Other nodal genes are directly or indirectly associated with the differentially expressed genes. The meaning of the nodal shapes is indicated.

Mentions: In order to gain an understanding of which functional cellular processes may be most affected during immunosenescence, genes that were significantly altered at TCC senescence were visualized by Ingenuity Pathway Analysis (IPA). Ingenuity entry tool systematically encodes findings presented in peer-reviewed scientific publications into ontologies, or groups of genes/proteins related by common function. A molecular network of direct physical, transcriptional, and enzymatic interactions was computed from this knowledge base. The resulting network contains molecular relationships with a high degree of connectivity and every gene in the network is supported by published information. Genes identified through microarray analysis (focus genes), network score (probability of network being assembled by chance alone), and main cellular functions of the network are listed in Table 5. The one statistically significant molecular network assembled using IPA profiling of genes differentially expressed in immunosenescence, including interacting partners, is depicted in Fig. 1. Genes demonstrated to be differentially expressed following microarray analysis of TCC senescence are coloured in grey. Class of function for each of the genes, including enzymes, growth factors, and receptors, are depicted by nodal shape, as identified in the figure legend.


Gene expression changes in long-term culture of T-cell clones: genomic effects of chronic antigenic stress in aging and immunosenescence.

Mazzatti DJ, White A, Forsey RJ, Powell JR, Pawelec G - Aging Cell (2007)

Network of genes differentially expressed in T-cell clone (TCC) immunosenescence. Forty-three genes that were differentially regulated in late passage, senescent, TCCs were analysed by the Ingenuity Pathway Analysis (IPA) tool. The network shown was significantly associated with cellular movement, haematological system development and function, immune response, cell-to-cell signaling and interaction, and cellular growth and proliferation (P < 0.01). Shaded genes were identified by microarray analysis as differentially expressed in TCC senescence. Other nodal genes are directly or indirectly associated with the differentially expressed genes. The meaning of the nodal shapes is indicated.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2049045&req=5

fig01: Network of genes differentially expressed in T-cell clone (TCC) immunosenescence. Forty-three genes that were differentially regulated in late passage, senescent, TCCs were analysed by the Ingenuity Pathway Analysis (IPA) tool. The network shown was significantly associated with cellular movement, haematological system development and function, immune response, cell-to-cell signaling and interaction, and cellular growth and proliferation (P < 0.01). Shaded genes were identified by microarray analysis as differentially expressed in TCC senescence. Other nodal genes are directly or indirectly associated with the differentially expressed genes. The meaning of the nodal shapes is indicated.
Mentions: In order to gain an understanding of which functional cellular processes may be most affected during immunosenescence, genes that were significantly altered at TCC senescence were visualized by Ingenuity Pathway Analysis (IPA). Ingenuity entry tool systematically encodes findings presented in peer-reviewed scientific publications into ontologies, or groups of genes/proteins related by common function. A molecular network of direct physical, transcriptional, and enzymatic interactions was computed from this knowledge base. The resulting network contains molecular relationships with a high degree of connectivity and every gene in the network is supported by published information. Genes identified through microarray analysis (focus genes), network score (probability of network being assembled by chance alone), and main cellular functions of the network are listed in Table 5. The one statistically significant molecular network assembled using IPA profiling of genes differentially expressed in immunosenescence, including interacting partners, is depicted in Fig. 1. Genes demonstrated to be differentially expressed following microarray analysis of TCC senescence are coloured in grey. Class of function for each of the genes, including enzymes, growth factors, and receptors, are depicted by nodal shape, as identified in the figure legend.

Bottom Line: Differentially expressed genes were confirmed by real-time polymerase chain reaction, and relationships between these assessed using Ingenuity Systems evidence-based association analysis.These pathways and affected genes may play a significant role in driving the cellular senescent phenotype and warrant further investigation as potential biomarkers of aging and senescence.These genes may additionally provide targets for intervention.

View Article: PubMed Central - PubMed

Affiliation: Unilever Corporate Research, Colworth Park, Sharnbrook, Bedford MK44 1LQ, UK. dawn.mazzatti@unilever.com

ABSTRACT
The adaptive immune response requires waves of T-cell clonal expansion on contact with altered self and contraction after elimination of antigen. In the case of persisting antigen, as occurs for example in cytomegalovirus or Epstein-Barr virus infection, this critical process can become dysregulated and responding T-cells enter into a dysfunctional senescent state. Longitudinal studies suggest that the presence of increased numbers of such T-cells is a poor prognostic factor for survival in the very elderly. Understanding the nature of the defects in these T-cells might facilitate intervention to improve immunity in the elderly. The process of clonal expansion under chronic antigenic stress can be modelled in vitro using continuously cultured T-cells. Here, we have used cDNA array technology to investigate differences in gene expression in a set of five different T-cell clones at early, middle and late passage in culture. Differentially expressed genes were confirmed by real-time polymerase chain reaction, and relationships between these assessed using Ingenuity Systems evidence-based association analysis. Several genes and chemokines related to induction of apoptosis and signal transduction pathways regulated by transforming growth factor beta (TGFbeta), epidermal growth factor (EGF), fos and beta-catenin were altered in late compared to early passage cells. These pathways and affected genes may play a significant role in driving the cellular senescent phenotype and warrant further investigation as potential biomarkers of aging and senescence. These genes may additionally provide targets for intervention.

Show MeSH
Related in: MedlinePlus