Defective Th function induced by a dominant-negative cAMP response element binding protein mutation is reversed by Bcl-2.
cAMP response element binding protein (CREB) is a critical regulator of diverse stimulus-dependent transcriptional events. Following TCR stimulation, CREB is rapidly induced in CD4+ Th cell precursors, but not in effector Th cells. However, its role in mature T cell function is incompletely defined. Transgenic mice expressing a CREB dominant-negative (dn) mutation in the T cell lineage exhibited normal T cell development in the thymus, normal T cell homeostasis in the periphery, and normal T cell clonal expansion following Ag challenge. However, this mutation caused selective inhibition of Th cell function in vitro and in vivo, and increased susceptibility of Th cells to activation-induced cell death. Th cells expressing the CREB-dn mutation contained reduced levels of the inhibitor of programmed cell death, BCL-2; overexpression of BCL-2 in transgenic mice reversed both susceptibility to activation-induced cell death in CREB-dn T cells and the defect in effector cytokine production. Thus, CREB plays a critical role in Th cell function and development of Th cell-mediated adaptive immune responses, at least in part, by inhibiting stimulus-dependent cell death.
Zhang
F
F
Division of Rheumatology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37025, USA.
Rincon
M
M
Flavell
R A
RA
Aune
T M
TM
D000409:Alanine / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D000818:Animals; D016923:Cell Death / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D006706:Homeostasis / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis; D007399:Interphase / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017354:Point Mutation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D012694:Serine / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D007376:Interleukin-2; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D012694:Serine; D000409:Alanine