The CD1 family of proteins serves as a molecular system for the presentation of the universe of lipid antigens to T cells. The five human CD1 isoforms include two groups:. Group I CD1 consists of the CD1a, b, and c molecules expressed on dendritic cells and found in humans and all other mammals except mice. Group 2 is represented by CD1d and found in all animals including mice. The physiologic function of CD1d is emerging and evidence exists supporting a role in host defense, immune tolerance, tumor immunity, and autoimmune disease such as systemic lupus, systemic sclerosis, and type I diabetes. In contrast, the group I CD1a, b, and c molecules are thought to provide for recognition of foreign microbial lipids. This proposal considers an alternative function of CD1a, b, and c, namely, presentation of self-lipids and the capacity to provoke immunoregulatory T cell functions bearing relationship to those proposed for the CDld-restricted T cell population. A large panel of cloned, autoreactive group 1 CD1-restricted T cells has been derived, which shares features of T cells restricted by CD1d. These clones secrete abundant cytokines in diverse patterns, are efficient cytolytic T cells, and express NK cell markers. Quantification of CD1 self-reactive cells ex vivo by ELISPOT indicates that this population is substantial. Surprisingly, a synthetic lipid spermicide, nonoxynol-9, was found to be a much more potent agonist than the self-lipid for one T cell clone. This suggested the hypothesis that self-lipid reactive CD1-restricted regulatory T cells might be influenced by exogenous lipids. Specifically, the illness in the epidemic "toxic oil syndrome" that occurred in Spain in 1981 was highly correlated with a contaminant closely matching the classic CD1 antigen general structure. Approximately 20% of patients with this syndrome went on to develop a chronic disease closely resembling scleroderma. Preliminary studies suggest that the toxic oil contaminants can promote T cell cytokine production in the presence of CD1-expressing immature dendritic cells. The long-term objectives of the proposed work are to structurally characterize foreign and self-lipid CD1 antigens, measure CD1 -restricted T cell responses in patients with scleroderma in comparison to healthy individuals, and identify therapeutic targets for amelioration of this disease by modulation of the immune system with candidate hydrophobic antigens. Just as previous work has focused on the role of CD1 a, b, and c in host defense against microbes, it is now possible, here, to begin to unravel the molecular basis for T cells autoreactive to self-lipids presented by CD1 a, b, and c.