VERMONT COBRE: PROJECT 1: INKT CELL ACTIVATION BY CD ID & ITS LIGANDS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Invariant natural killer T (iNKT) cells comprise a novel subset of regulatory lymphocytes that has a profound effect on infectious disease, autoimmunity, tolerance induction, and tumor immunology. The long term goal of our research is to understand the fundamental basis governing iNKT cell specificity for its CDld-bound ligand(s). All human iNKT cells express an unusual T cell receptor consisting of an invariant Va24Jo.l 8 alpha chain paired with ajunctionally diverse Vpll beta chain. Nearly all iNKT cells are activated by ¿- galactosylceramide (aGalCer), a synthetic glycosphingolipid that is not found in vertebrates. The identity of natural activating ligands in mammals has remained elusive. We will test the hypothesis that the human activating endogenous CD Id ligands are a heterogeneous set of glycosphingolipids that form overlapping but distinct interactions with aGalCer-reactive iNKT TCRs. This hypothesis is based on the observations that iNKT cells can recognize tissue-specific ligands, and that while all iNKT cells arc activated by aGalCer, some, but not all, iNKT cells are activated in the presence and in the absence of aGalCcr. Presumably these latter iNKT cells are able to recognize both aGalCer and unidentified natural activating ligands. To test our hypothesis we will: i) Characterize the contribution of the semi-invariant TCR alpha and beta chains to iNKT cell recognition of natural and synthetic CD Id ligands, and ii) define biosynthetic pathways and the heterogeneity of glycosylceramides used in the formation of natural CDld ligands and/or their precursors. The ability of iNKT cells to exert their effects over a wide irnmunological spectrum makes them ideal targets for immunotherapy. The experiments in this proposal will provide the detailed undcrstt.nding of the fundamental interactions of iNKT TCRs with their CDld-bound ligands necessary for the rational design of such therapies.