Gender-Specific Expression of β1 Integrin of VLA-4 in Myelin Basic Protein-Primed T Cells: Implications for Gender Bias in Multiple Sclerosis

Susceptibility to multiple sclerosis is higher in females than males. However, the underlying mechanism behind this gender difference is poorly understood. Because the presence of neuroantigen-primed T cells in the CNS is necessary to initiate the neuroinflammatory cascade of multiple sclerosis, we first investigated how these T cells interacted with astroglia, major resident glial cells of the CNS. Interestingly, we found that myelin basic protein (MBP)-primed T cells from female and castrated male mice, but not from male mice, produced proinflammatory molecules, such as NO, IL-1 beta, and IL-6 in astroglia, and these responses were purely via contact between T cells and astroglia. Because T cell: glia contact requires several integrin molecules, we examined the involvement of integrins in this process. Both alpha 4 and beta 1, subunits of VLA-4 integrin, were found to be necessary for T cell contact-induced generation of proinflammatory molecules in astroglia. Interestingly, the expression of beta, but not alpha 4, was absent in male MBP-primed T cells. In contrast, female and castrated male MBP-primed T cells expressed both alpha 4 and beta. Similarly, we also detected beta 1 in spleen of normal young female, but not male, mice. Furthermore, we show that male sex hormones (testosterone and dihydrotestosterone), but not female sex hormones (estrogen and progesterone), were able to suppress the mRNA expression of beta 1 in female MBP-primed T cells. These studies suggest that beta 1, but not alpha 4, integrin of VLA-4 is the sex-specific molecule on T cell surface, and that the presence or absence of beta 1 determines gender-specific T cell contact-mediated glial activation. The Journal of Immunology, 2010, 184: 6103-6113.