The objective of this proposal is to investigate the immunoregulatory role of natural killer (NK) cells in Multiple Sclerosis (MS). NK cells are important effector cells participating in the protection against viruses and the development of malignancies. However, NK cells appear to be critically involved in the crosstalk between innate and adaptive immune responses and may help to maintain immune tolerance. Important defects in NK numbers and/or function have been reported in patients with autoimmune disorders, including MS, and in animals susceptible to induction of autoimmunity. Additionally, several therapeutic agents that were shown to effectively suppress inflammation in MS (IFN-beta, linomide and Daclizumab) stimulate NK cell function. However, the mechanism(s) by which NK cells may participate in the maintaining of the immune tolerance remain undefined. We hypothesize that the defective immunoregulation of T cell responses by NK cells is an important factor in MS pathogenesis. Our long-term goal is to apply mechanistic insight into NK-mediated immunoregulation to develop new/more effective therapies for MS. The goal of this application is to elucidate the key cellular and molecular mechanisms and rules of interaction between human NK cells and T cells in order to determine if NK-mediated regulation of T cell responses is important for the maintenance of immune tolerance under physiological conditions. Additionally, we want to determine if NK-mediated immunoregulatory mechanisms are deficient in untreated MS patients and whether Daclizumab therapy restores these deficiencies. This goal will be achieved in 3 Specific Aims: (1) Determine the effect of NK cells on T cell priming toward Th17 phenotype; (2) Define the extent and mechanism of NK-mediated killing of autoreactive T cells and (3) Determine the in vivo relevance of the NK-mediated mechanisms of immunoregulation defined in Aims 1&2 by analyzing paired baseline and treatment samples from the Phase II clinical trial of Daclizumab monotherapy in untreated MS patients, and by correlating the effect of Daclizumab on these immunoregulatory mechanisms with clinical and paraclinical (i.e. MRI) measures of their MS disease activity. These studies will provide new insight into how NK cells participate in the maintenance of immune tolerance and how deficiencies in NK cell function can lead to the development of autoimmunity. We expect that this knowledge will translate into the development of new therapies for MS and other autoimmune diseases. [unreadable] [unreadable] [unreadable]