| The immunostimulatory outcome of the interactions of many pathogens with dendritic cells (DC) has been well characterized. There are many fewer examples of similar interactions between DC and self-molecules, especially the abnormal self-proteins such as many tumor antigens, and their effects on DC function and the immune response. We show that human epithelial cell antigen MUC1 mucin, is recognized in its aberrantly glycosylated form on tumor cells by immature human myeloid DC as both a chemoattractant (through its polypeptide core) and a maturation and activation signal (through its carbohydrate moieties). Interestingly, MUC1 is chemotactic for immature DC but not for other cells of the immune system. Not only is this the first example of a tumor antigen that has chemotactic abilities but there are also no known receptors that are expressed uniquely on immature DC. However, we have determined that the MUC1 chemotactic receptor is a member of the chemokine receptor family based on its sensitivity to pertussis toxin, the formation of pseudopods upon ligand binding, and the Ca2+ flux in response to MUC1. Upon encounter with MUC1, similar to the encounter with LPS, immature DC increase cell surface expression of CD80, CD86, CD40 and CD83 molecules and the production of IL-6 and TNF-alpha cytokines, but fail to make IL-12. When these DC are co-cultured with allogeneic CD4+ T cells, they induce production of IL-13 and IL-5 and lower levels of IL-2, thus failing to induce a type 1 response. Our data suggest that in cancer patients in vivo, MUC1 attracts immature DC to the tumor through chemotaxis and then subverts their function by negatively affecting their ability to stimulate type 1 helper T cell responses important for tumor rejection.*; *This dissertation is a compound document (contains both a paper copy and a CD as part of the dissertation). |
