Myelin Basic Protein-primed T Helper 2 Cells Suppress Microglial Activation via AlphaVBeta3 Integrin: Implications for Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is the most common autoimmune demyelinating disease in human and T helper type 2 (Th2) cells have been shown to be beneficial for this disease. However, mechanisms by which Th2 cells ameliorate disease in MS are poorly understood. Microglial activation plays an important role in the pathogenesis of MS and other neurodegenerative disorders. Here, we delineate that Th2 cells are capable of suppressing microglial activation via cell-to-cell contact. After polarization of MBP-primed Th1 cells to Th2 by gemfibrozil and other drugs, we observed that MBP-primed Th2 cells dose dependently inhibited the production of interleukin-1β (IL-1β) and nitric oxide (NO) in LPS-stimulated microglia via cell-to-cell contact. Similarly, Th2 cells also suppressed the microglial inflammatory response in the presence of different pathological stimuli of Alzheimer's disease (AD), Parkinson's disease (PD), and HIV associated dementia (HAD). Interestingly, Th2 cells expressed higher levels of alphaV (αV) and beta3 (β3) integrins as compared to Th1 cells, and functional blocking antibodies against αV and β3 integrins impaired the ability of Th2 cells to suppress microglial activation. Furthermore, we demonstrate that microglia expressed the beta subunit of PDGF receptor (PDGFRβ) and that neutralization of PDGFRβ abrogated the ability of Th2 cells to suppress microglial inflammation. Activation of microglial cAMP response element-binding (CREB) by Th2 cells, suppression of CREB activation by neutralization of either αV and β3 integrins on Th2 cells or PDGFRβ on microglia, abrogation of anti-inflammatory activity of Th2 cells by siRNA knockdown of microglial CREB, highlights the importance of αVβ3 and PDGFRβ in guiding the anti-inflammatory activity of Th2 cells via activation of CREB, which may be responsible for beneficial effect of Th2 cells in MS and other related disorders.