Chemokine and matrix metalloproteinase secretion by myelin proteolipid protein-specific CD8+ T cells: potential roles in inflammation

Abstract

The demyelination process that occurs in the central nervous system of patients with multiple sclerosis (MS) is, in part, due to an inflammatory response in which CD4+ and CD8+ T cells and macrophages infiltrate white matter. Although many studies have characterized myelin protein-specific CD4+ T cells, we have demonstrated that CD8+ CTL specific for myelin peptides can be identified. In the present study, the potential roles of these CD8+ CTL in the generation of the inflammatory responses associated with MS have been investigated by measuring the capacity of these T cells to secrete the following proinflammatory chemokines: macrophage inflammatory protein-1alpha (MIP-1alpha) and MIP-1beta, lymphocyte chemoattractant factor (IL-16), IFN-inducible protein-10, as well as the proinflammatory enzymes of the matrix metalloproteinase family. The CD8+ CTL lines tested are derived from MS patients and are specific for two different myelin proteolipid protein-derived peptides presented by HLA-A2 and HLA-A3. All of the 17 CD8+ CTL lines secreted detectable amounts of MIP-1alpha and MIP-1beta. Nine of twelve CTL lines tested secreted IL-16, 10 of 12 lines tested secreted IFN-inducible protein-10, and 14 of 16 lines tested secreted matrix metalloproteinase-9. Collectively, these results indicate that myelin proteolipid protein peptide-specific CD8+ CTL may be an important source of proinflammatory soluble mediators that could promote and mediate the inflammatory response in MS demyelination.