The T-cell subsets, characterized by their cytokine production profiles and immune regulatory functions, depend on correct in vivo location to interact with accessory or target cells for effective immune responses. Differentiation of naive CD4 1 T cells into effectors is accompanied by sequentially regulated expression of the chemokine receptors responsible for cell recruitment to specific tissues. We studied CCR6 function in EAE, a CD4 1 T-cell-mediated CNS disease characterized by mononuclear infiltration and demyelination. CCR6 À/À mice showed an altered time course of EAE development, with delayed onset, a higher clinical score, and more persistent symptoms than in controls. An imbalanced cytokine profile and reduced Foxp3 1 cell frequency characterized CNS tissues from CCR6 À/À compared with CCR6 1/1 mice during the disease effector phase. Transfer of CCR6 1/1 Treg to CCR6 À/À mice the day before EAE induction reduced the clinical score associated with an increased in infiltrating Foxp3 1 cells and recovery of the cytokine balance in CCR6 À/À mouse CNS. Competitive assays between CCR6 1/1 and CCR6 À/À Treg adoptively transferred to CCR6 À/À mice showed impaired ability of CCR6 À/À Treg to infiltrate CNS tissues in EAE-affected mice. Our data indicate a CCR6 requirement by CD4 1 Treg to downregulate the CNS inflammatory process and neurological signs associated with EAE.Key words: Chemokines . EAE/MS . Inflammation . T cells Introduction EAE is a CNS disease characterized by mononuclear cell infiltration and demyelination; it is used to study certain aspects of human MS. EAE can be induced via immunization with neural antigens such as myelin oligodendrocyte glycoprotein (MOG). The immunopathological event in EAE and MS initiates when autoreactive T cells in the systemic immune compartment are activated and cross the blood-brain barrier [1]. Re-encounter of encephalitogenic T cells with their antigen leads to reactivation and expansion of autoreactive T cells, which in turn stimulate microglia/astrocyte activity, with increased release of proinflammatory cytokines and chemokines. The action of these mediators leads to demyelination and axon degeneration [2,3]. After antigen contact, naive CD4 1 T cells differentiate into various effector-cell subsets characterized by the cytokines they produce and by their immune regulatory functions. Th1 and Th17 cytokine profile effector cells and antigen-specific Treg have a critical role in EAE pathogenesis [4][5][6][7][8][9][10]. In MOG-induced EAE, both antigen-specific T-effector and Treg differentiate and proliferate in the periphery before migrating to the CNS [9]. Differentiation is accompanied by sequential expression of selectins, integrins, and chemokine receptors responsible for T-cell-subset recruitment to and extravasation at inflammation sites. The correct in vivo location of these cell subsets, necessary for their interaction with accessory or target cells, is regulated by [11], which are assumed to have a critical impact on MS and EAE pathogenesis [12]. St...