Defective signaling in a subpopulation of CD4(+) T cells in the absence of Ca(2+)/calmodulin-dependent protein kinase IV.
Ca(2+)/calmodulin-dependent protein kinase IV-deficient (CaMKIV(-/-)) mice have been used to investigate the role of this enzyme in CD4(+) T cells. We identify a functional defect in a subpopulation of CD4(+) T cells, characterized by a cell surface marker profile usually found on memory phenotype CD4(+) T cells. Upon T-cell receptor engagement, the mutant cells produce diminished levels of interleukin-2 (IL-2), IL-4, and gamma interferon protein and mRNA. The defect is secondary to an inability to phosphorylate CREB and to induce CREB-dependent immediate-early genes, including c-jun, fosB, fra2, and junB, which are required for cytokine gene induction. In contrast, stimulated naive CD4(+) T cells from CaMKIV(-/-) mice show normal CREB phosphorylation, induction of immediate-early genes, and cytokine production. Thus, in addition to defining an important signaling role for CaMKIV in a subpopulation of T cells, we identify differential signaling requirements for cytokine production between naive T cells and T cells that express cell surface markers characteristic of the memory phenotype.
Anderson
Kristin A
KA
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 22710, USA.
Means
Anthony R
AR
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000502:physiology*; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010641:Phenotype; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D015847:Interleukin-4; D007371:Interferon-gamma; D019893:Ribosomal Protein S6 Kinases; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517685:Camk4 protein, mouse