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(1) protein-linked receptors that induce a signaling cascade in human T cells and provide costimulation for T cell activati on, in addition to participating in transendothelial migration of leuk ocytes. 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 presen ce of macrophage inflammatory protein-1 alpha(MIP-1 alpha) showed enha nced IFN-gamma 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 stimula ted with anti-CD3 mAb or OVA peptide. Primary stimulation of T cells i n the presence of chemokines, followed by secondary stimulation and te rtiary stimulation with anti-TCR clonotype mAb alone (no exogenous che mokines), revealed an enhanced IFN-gamma production for MIP-alpha stim ulation and IL-4 production for MCP-1 stimulation. Naive Tg(+) T cells , obtained from Tg(+) mice crossed to RAG-1-deficient mice, showed enh anced IFN-gamma production when incubated with MIP-1 alpha and enhance d 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.