Role of very-late antigen-4 (VLA-4) in myelin basic protein-primed T cell contact-induced expression of proinflammatory cytokines in microglial cells

The presence of neuroantigen- primed T cells recognizing self- myelin antigens within the CNS is necessary for the development of demyelinating autoimmune disease like multiple sclerosis. This study was undertaken to investigate the role of myelin basic protein ( MBP)primed T cells in the expression of proinflammatory cytokines in microglial cells. MBP- primed T cells alone induced specifically the microglial expression of interleukin (IL)-1beta, IL-1alpha tumor necrosis factor alpha, and IL- 6, proinflammatory cytokines that are primarily involved in the pathogenesis of MS. This induction was primarily dependent on the contact between MBP- primed T cells and microglia. The activation of microglial NF-kappaB and CCAAT/ enhancer- binding protein beta ( C/ EBPbeta) by MBP-primed T cell contact and inhibition of contact- mediated microglial expression of proinflammatory cytokines by dominant- negative mutants of p65 and C/ EBPbeta suggest that MBP- primed T cells induce microglial expression of cytokines through the activation of NF- kappaB and C/EBPbeta. In addition, we show that MBP- primed T cells express very late antigen- 4 ( VLA- 4), and functional blocking antibodies to alpha(4) chain of VLA- 4 ( CD49d) inhibited the ability of MBP- primed T cells to induce microglial proinflammatory cytokines. Interestingly, the blocking of VLA- 4 impaired the ability of MBP- primed T cells to induce microglial activation of only C/ EBPbeta but not that of NF-kappaB. This study illustrates a novel role of VLA- 4 in regulating neuroantigen- primed T cell- induced activation of microglia through C/ EBPbeta.