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Administration of daclizumab, a humanized mAb directed against the IL-2Rα chain, strongly reduces brain inflammation in multiple sclerosis patients. Here we show that daclizumab treatment leads to only a mild functional blockade of CD4⁺ T cells, the major candidate in multiple sclerosis pathogenesis. Instead, daclizumab therapy was associated with a gradual decline in circulating CD4⁺ and CD8⁺ T cells and significant expansion of CD56^bright natural killer (NK) cells in vivo, and this effect correlated highly with the treatment response. In vitro studies showed that NK cells inhibited T cell survival in activated peripheral blood mononuclear cell cultures by a contact-dependent mechanism. Positive correlations between expansion of CD56^bright NK cells and contraction of CD4⁺ and CD8⁺ T cell numbers in individual patients in vivo provides supporting evidence for NK cell-mediated negative immunoregulation of …