The overall objective of this application is to determine the nature of ligands recognized by gamma/delta T-cells, and to ascertain the functional importance of gamma/delta T-cells responses to their ligand. Based on their previous findings and on others reported in the literature, we hypothesize that one groups of gamma/delta TCR ligands consists of soluble heterologous molecules that contain repetitive stimulatory patterns, or that aggregate to form such patterns, and which do not require presentation in order to be stimulatory. These ligands, which they have dubbed group 3 ligands, resemble and may include the type 2 T-cell-independent antigens of B-cells. They describe here two group 3 ligands that stimulate similar or identical subsets of gamma/delta T-cells: poly Glu50Tyr50 (pEY, historically termed """"""""poly-GT""""""""), a synthetic hetero-copolymeric peptide antigen; and cardiolipin (CL), a natural phospholipid present in prokaryotic and mitochondrial but not eukaryotic membranes. Although not a natural ligand, pEY, being a polypeptide, can easily be chemically modified and attached to other structures, and thus lends itself well to experiments designed to determine how group 3 antigens stimulate gamma/delta T-cells, and what is required for the stimulation. Thus, for mechanistic studies, they plan to focus on pEY as a model group 3 gamma/delta T-cell antigen, then return to CL, a natural ligand likely to be present during bacterial infection or inflammatory cell damage, to establish whether gamma/delta T-cell responses to group 3 antigens are important in immunobiology. Because of the probable overlap between group 3 gamma/delta T-cell ligands and B-cell type 2 T-cell-independent antigens, we anticipate that gamma/delta T-cells might in some circumstances be important in the development of antibody responses to certain immunogens.
The specific aims of this application are: 1. To define the mechanism by which pEY elicits responses of gamma/delta T-cells. 2. To characterize the response of normal gamma/delta T-cells to pEY and related antigens, and the ability of such cells to support antibody responses. 3. To test whether gamma/delta T-cells also respond to established type 2 T-cell-independent antigens, and whether they influence the reactivity of marginal zone B-cells to these antigens. 4. To establish the phospholipid cardiolipin as an antigen for innate gamma/delta T-cell responses, and to investigate the role of gamma/delta T-cells in the development of pathogenic anti-phospholipid antibodies.
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