Kevin J. Kennedy

Chemokines are a family of small m.w. cytokines that induce chemotaxis and chemokinesis of leukocytes. These molecules are ligands for seven-transmembrane, Gi 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-1alpha (MIP-1alpha) showed enhanced 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 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-gamma production for MIP-1alpha 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-gamma production when incubated with MIP-1alpha 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.

Chemokines are a family of small-molecular-weight cytokines that induce chemotaxis and chemokinesis of leukocytes. These molecules are ligands for seven-transmembrane, G-protein-linked receptors and are known to activate integrins on the surface of leukocytes and other cells as well as induce a number of signaling events. They play a significant role in the migration of leukocytes from blood into tissue during inflammatory processes. We tested the role of chemokines in experimental autoimmune encephalomyelitis (EAE) and found that macrophage inflammatory protein-1alpha (MIP-1alpha) correlated with acute disease development, whereas monocyte chemotactic protein-1 (MCP-1) did not. In contrast, MCP-1 production in the central nervous system correlated with relapsing EAE development. Moreover, anti-MIP-1alpha, but not anti-MCP-1, inhibited development of acute but not relapsing EAE, whereas anti-MCP-1 significantly reduced the severity of relapsing EAE. To test the effects of chemokines on the differentiation of naive T cells, TCR transgenic splenic T cells (Tg+ T cells) from DO11.10 OVA TCR transgenic mice were used as a source of Th0 cells and were stimulated with specific anti-clonotypic monoclonal antibodies in the presence of MIP-1alpha, MCP-1, or controls. MIP-1alpha drove Th0 cells to differentiate to Th1, whereas MCP-1 drove Th0 cells to differentiate to Th2. Similarly, MCP-1, but not MIP-1alpha significantly inhibited the adoptive transfer of EAE when included in in vitro activation cultures, further suggesting a regulatory anti-inflammatory property. These results suggest a differential role for CC chemokines in the development and activation of T cells during autoimmune inflammatory diseases.

Experimental autoimmune encephalomyelitis (EAE) is a CD4(+) Th1-mediated demyelinating disease of the CNS that serves as a model for multiple sclerosis. A critical event in the pathogenesis of EAE is the entry of both Ag-specific and Ag-nonspecific T lymphocytes into the CNS. In the present report, we investigated the role of the CXC chemokine CXCL10 (IFN-gamma-inducible protein-10) in the pathogenesis of EAE. Production of CXCL10 in the CNS correlated with the development of clinical disease. Administration of anti-CXCL10 decreased clinical and histological disease incidence, severity, as well as infiltration of mononuclear cells into the CNS. Anti-CXCL10 specifically decreased the accumulation of encephalitogenic PLP(139-151) Ag-specific CD4+ T cells in the CNS compared with control-treated animals. Anti-CXCL10 administration did not affect the activation of encephalitogenic T cells as measured by Ag-specific proliferation and the ability to adoptively transfer EAE. These results demonstrate an important role for the CXC chemokine CXCL10 in the recruitment and accumulation of inflammatory mononuclear cells during the pathogenesis of EAE.