Block of T lymphocyte differentiation by activation of the cAMP-dependent signal transduction pathway.
Differentiation of T lymphocytes is a complex and finely tuned process. Here we show that treatment of mouse fetal thymus organ cultures with agents activating the cAMP-dependent signalling pathway results in the block of thymocyte differentiation. This is due to severe impairment of maturation beyond the CD4-/CD8- stage. In addition, rearrangements at the TCR alpha gene locus, but not at the TCR beta locus, are completely inhibited. The cAMP effect is reversible and is restricted to TCR alpha beta+ cells. cAMP acts both by triggering apoptosis and by inducing cell-cycle block in thymocytes. Thus, activation of the cAMP pathway provides a mechanism to modulate thymic function for hormones and ligands whose receptors are coupled to adenylate cyclase.
Lalli
E
E
Institut de Génétique et Biologie Moléculaire et Cellulaire, CNRS-INSERM-ULP, Strasburg, France.
Sassone-Corsi
P
P
Ceredig
R
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001483:Base Sequence; D003994:Bucladesine / Q000494:pharmacology; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology* / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D017931:DNA Primers / Q000235:genetics; D004791:Enzyme Inhibitors / Q000378:metabolism; D015332:Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor / Q000187:drug effects; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor / Q000187:drug effects; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D008969:Molecular Sequence Data; D009924:Organ Culture Techniques; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction / Q000276:immunology* / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects; D025521:Tumor Suppressor Proteins; D019061:src-Family Kinases / Q000378:metabolism
D015704:CD4 Antigens; D016827:CD8 Antigens; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D017931:DNA Primers; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003994:Bucladesine; D000242:Cyclic AMP; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases