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An approach to the analysis of gene expression in chronically activated T Lymphocytes

We have been studying the intracellular signaling pathways in chronically activated T cells involved in effector responses and promoting the inflammatory process, and have been struck by the extent to which T cells stimulated with TNF for prolonged periods in vitro resemble RA synovial T cells. For example, TNF upregulates expression of the activation antigen CD69, induces non-deletional and reversible hyporesponsiveness to TCR ligation by uncoupling proximal TCR signalling pathways, and represses CD28 gene expression. We have explored the possibility that systematic expression profiling of murine T cell hybridomas stimulated with pM concentrations of TNF under controlled conditions might provide further insight into the phenotype and function of cytokine activated T cells, as well as the mechanisms through which TNF uncouples TCR signal transduction pathways. Expression profiling has been performed using medium density spotted arrays based on the Compugen™ gene set. This comprises 9,215 oligonucleotide 50-mer elements including housekeeping genes and "landing lights", and covers 7,524 known mouse genes (representing 17K RNAs and 303K ESTs). Genes whose expression are altered by TNF treatment have been identified by measuring the fluorescence ratio of Cy5- and Cy3-labeled target cDNA bound to each probe following hybridization of differentially labeled cDNA pools, prepared from TNF stimulated (Cy5) or control (Cy3) T cells. Based on this simplistic analysis, clusters of genes that appear to be differentially regulated in chronic TNF treated T cells have been identified and were found to include genes whose products may function to potentiate the inflammatory response. We report that the expression signature for chronic TNF stimulation suggests a phenotype which promotes cell survival, while enhancing Th1 differentiation, recruitment to sites of inflammation and effector responses. We are now analysing data from experiments designed to explore the possibility that this particular gene expression signature is distinct from the programme of gene transcription arising from short term TNF stimulation. We anticipate that this approach may provide further insight into the molecular mechanisms which promote chronic, as opposed to acute inflammatory responses.

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Cope, A., Clark, J., Panesar, M. et al. An approach to the analysis of gene expression in chronically activated T Lymphocytes. Arthritis Res Ther 4 (Suppl 1), 19 (2002).

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