Myelin basic protein-primed T cells induce neurotrophins in glial cells via alphavbeta3 [corrected] integrin.
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 alpha5 and beta3 integrins and functional blocking antibodies against both alpha5 and beta3 integrins inhibited the ability of MBP-primed Th2 cells to induce glial neurotrophins. On the other hand, glial cells expressed PDGF-Rbeta 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 alpha5beta3 integrins on T cells or PDGF-Rbeta 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 alpha5beta3 and PDGF-Rbeta 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.
Roy
Avik
A
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, USA.
Liu
Xiaojuan
X
Pahan
Kalipada
K
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002469:Cell Separation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005260:Female; D015248:Gemfibrozil / Q000494:pharmacology; D007155:Immunologic Factors / Q000494:pharmacology; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D017628:Microglia / Q000378:metabolism; D004676:Myelin Basic Protein / Q000276:immunology*; D009457:Neuroglia / Q000378:metabolism*; D020933:Neurotrophin 3 / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology*