Defective Signaling in a Subpopulation of CD4⁺ T Cells in the Absence of Ca²⁺/Calmodulin-Dependent Protein Kinase IV

Abstract

Ca²⁺/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.

We are grateful to Bob Abraham for critically reading the manuscript. We also thank Mike Cook of the Duke Cancer Center Core Flow Cytometry Facility for performing the FACS analysis.

This work was supported by NIH grant HD-07503.