Defective Signaling in a Subpopulation of CD4 + T Cells in the Absence of Ca 2+ /Calmodulin-Dependent Protein Kinase IV

Abstract

ABSTRACT 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.