CD1 proteins and glycolipid antigens activate human T cells during the natural course of human infectious and autoimmune diseases such as tuberculosis infection and autoimmune diabetes. The proposed functions of CD1-restricted T cells in tumor immunity, infection and autoimmunity are based on the premise that infection or other cellular perturbations lead to the presentation of microbial or altered self antigens that differ in structure from in the larger pool of self glycolipids that normally comprise cell membranes. However, the particular chemical features of natural glycolipids that control their loading onto CD1 proteins and recognition by T cells are not known. The first known antigens presented by CD1c have recently been described by investigator to be an evolutionarily conserved family of polyisoprenoid glycolipids including mannosyl phosphodolichol (MPD). These antigens were originally isolated from the cell walls of pathogenic mycobacteria, but they have strong structural homology to human MPD, self glycolipid found in all human cells. Preliminary data now demonstrate that MPD, which is similar or identical in structure to human MPD activates CD1c-restricted T cells, including T cells that were previously thought to be autoreactive to CD1c Furthermore, human tissues that are rich in dolichyl glycolipids are infiltrated by CD1c-expressing antigen presenting cells and CD1 c-restricted, MPD-dependent T cells during the normal course of autoimmune thyroiditis. Therefore, the investigator hypothesizes that CD1c-MPD complexes are a molecular target of autoimmune T cell responses in vivo. This will be tested by eluting endogenous glycolipids from cellular CD1 c proteins and measuring the ability of purified dolichyl glycolipids to bind to CD1c in vitro. The ability of mammalian cells to generate antigenic CD1 c-MPD complexes from endogenous glycolipids will be assessed by T cell recognition of cells that are genetically engineered to produce altered MPD. The precursor frequency of antigen specific lymphocytes from human patients with autoimmune thyroiditis will be measured using intracellular cytokine stains and CD1c tetramers. This will test the hypothesis that CD1c and MPD reactive T cells are activated during a human autoimmune disease that targets dolichol-rich tissues. These studies will define the molecular features of natural self and foreign dolichyl glycolipids that control the separate processes of binding to CD1c and activation of T cells.
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