Gene regulation mediated by calcium signals in T lymphocytes.
Modulation of many signaling pathways in antigen-stimulated T and B cells results in global changes in gene expression. Here we investigate the contribution of calcium signaling to gene expression in T cells using cell lines from two severe-combined immunodeficiency patients with several cytokine deficiencies and diminished activation of the transcription factor NFAT nuclear factor of activated T cells. These T cells show a strong defect in transmembrane calcium influx that is also apparent in their B cells and fibroblasts. DNA microarray analysis of calcium entry-deficient and control T cells shows that Ca2+ signals both activate and repress gene expression and are largely transduced through the phosphatase calcineurin. We demonstrate an elaborate network of signaling pathways downstream of the T cell receptor, explaining the complexity of changes in gene expression during T cell activation.
Center for Blood Research and Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
S
S
Feske
J
J
Giltnane
R
R
Dolmetsch
L M
LM
Staudt
A
A
Rao
D001402:B-Lymphocytes / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism; D020013:Calcium Signaling; D002460:Cell Line; D016207:Cytokines / Q000172:deficiency; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008213:Lymphocyte Activation; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D020411:Oligonucleotide Array Sequence Analysis; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D016207:Cytokines; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D019703:Calcineurin