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J. Biol. Chem., Vol. 277, Issue 42, 39327-39333, October 18, 2002

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Myelin Basic Protein-primed T Cells Induce Nitric Oxide Synthase in Microglial Cells
IMPLICATIONS FOR MULTIPLE SCLEROSIS^*

Subhajit Dasgupta, Malabendu Jana, Xiaojuan Liu, and Kalipada Pahan

From the Department of Oral Biology, University of Nebraska Medical Center, Lincoln, Nebraska 68583

The presence of autoreactive T cells recognizing self myelin antigens is necessary for the development of central nervous system autoimmune diseases such as multiple sclerosis (MS). The present study was undertaken to investigate the role of myelin basic protein (MBP)-primed T cells in the expression of inducible nitric oxide synthase (iNOS) in microglial cells. MBP-primed T cells alone markedly induced the production of NO and the expression of iNOS protein and mRNA in mouse BV-2 microglial cells. Similarly, MBP-primed T cells also induced the production of NO in mouse primary microglia. This induction of NO production was primarily dependent on the contact between MBP-primed T cells and microglia. The expression of very late antigen-4 (VLA-4) on the surface of MBP-primed T cells and inhibition of MBP-primed T cell-induced microglial NO production by functional blocking of antibodies to the ₄ chain of VLA-4 (CD49d) suggest that VLA-4 integrin on MBP-primed T cells plays an important role in contact-mediated induction of iNOS. Since IFN- has been used to treat MS patients, we examined the effect of IFN- on MBP-primed T cell-induced the production of NO. Surprisingly, IFN- alone induced the production of NO in microglial cells. However, the pretreatment of MBP-primed T cells with IFN- inhibited the expression of VLA-4 integrin on the surface of MBP-primed T cells and thereby inhibited the ability of those T cells to induce the production of NO in microglial cells. This study illustrates a novel role of neuroantigen-primed T cells in inducing contact-mediated expression of iNOS in microglial cells that may participate in the pathogenesis of MS.

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