Differential CC Chemokine-Induced Enhancement of T Helper Cell Cytokine Production

Chemokines are a family of small m.w. cytokines that induce chemotaxis and chemokinesis of leukocytes. These molecules are ligands for seven-transmembrane, G_j protein-linked receptors that induce a signaling cascade in human T cells and provide costimulation for T cell activation, in addition to participating in transendothelial migration of leukocytes. To address the role of chemokines in the regulation of Th cell cytokine production, we utilized an OVA-specific TCR transgenic (Tg⁺) model. Cells stimulated through the TCR and incubated in the presence of macrophage inflammatory protein-1α (MIP-1α) showed enhanced IFN-γ production, whereas cells incubated in the presence of monocyte chemotactic protein-1 (MCP-1) showed enhanced IL-4 production. Similar results were obtained whether TCR Tg⁺ T cells were stimulated with anti-CD3 mAb or OVA peptide. Primary stimulation of T cells in the presence of chemokines, followed by secondary stimulation and tertiary stimulation with anti-TCR clonotype mAb alone (no exogenous chemokines), revealed an enhanced IFN-γ production for MIP-1α stimulation and IL-4 production for MCP-1 stimulation. Naive Tg⁺ T cells, obtained from Tg⁺ mice crossed to RAG-1-deficient mice, showed enhanced IFN-γ production when incubated with MIP-1α and enhanced IL-4 production when incubated with MCP-1. These results suggest CC chemokines play a role in regulating naive Th cell cytokine production, in addition to regulating leukocyte trafficking.