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J. Biol. Chem., Vol. 282, Issue 44, 32222-32232, November 2, 2007

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Myelin Basic Protein-primed T Cells Induce Neurotrophins in Glial Cells via 53 Integrin^*

Avik Roy, Xiaojuan Liu, and Kalipada Pahan¹

From the Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612 and the Section of Neuroscience, Department of Oral Biology, University of Nebraska Medical Center College of Dentistry, Lincoln, Nebraska 68583

Increasing the level of neurotrophins within the central nervous system may have therapeutic efficacy in patients with various neurological diseases. Earlier we have demonstrated that myelin basic protein (MBP)-primed T cells induce the expression of various proinflammatory molecules in glial cells via cell-to-cell contact. Here we describe that after Th2 polarization by gemfibrozil or other drugs, MBP-primed T cells induced the expression of neurotrophic molecules such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), but not proinflammatory molecules in microglia and astroglia via cell-to-cell contact. MBP-primed Th2 cells expressed 5 and 3 integrins and functional blocking antibodies against both 5 and 3 integrins inhibited the ability of MBP-primed Th2 cells to induce glial neurotrophins. On the other hand, glial cells expressed PDGF-R and neutralization of this glial receptor abrogated the ability of Th2 cells to induce neurotrophins in glia. Activation of glial cAMP response element-binding protein (CREB) by MBP-primed Th2 cell contact and inhibition of contact-mediated expression of neurotrophins by antisense knockdown of glial CREB suggest that MBP-primed Th2 cell-glia contact induces the expression of neurotrophins through glial activation of CREB. Accordingly, blocking of either 53 integrins on T cells or PDGF-R on glial cells impaired the ability of MBP-primed Th2 cells to induce glial activation of CREB. Furthermore, we demonstrate that these MBP-primed Th2 cells entered into the central nervous system and increased the expression of neurotrophins in vivo in the brain. This study illuminates the importance of 53 and PDGF-R in guiding the novel neurotrophic property of neuroantigen-primed T cells via activation of CREB that may be of therapeutic importance in various neurological disorders.

Received for publication, April 5, 2007 , and in revised form, August 13, 2007.

^* This study was supported in part by grants from the National Multiple Sclerosis Society (RG3422A1/1), National Institutes of Health (NS39940 and NS48923), and Michael J. Fox Foundation for Parkinson Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ To whom correspondence should be addressed: Dept. of Neurological Sciences, Rush University Medical Center, Cohn. Res. Bldg., Suite 320, 1735 West Harrison St., Chicago, IL 60612. Tel.: 312-563-3592; Fax: 312-563-3571; E-mail: Kalipada_Pahan{at}rush.edu.

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