Immunobiology of NKT cell development and function

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Invariant Natural Killer T cells (iNKT cells) are a rare but potent population of cells expressing features in common with both natural killer cells and T cells. These CD1d restricted cells have been shown to both positively and negatively modulate immune responses. Roles for iNKT cells range from fighting tumors to suppressing or curing various autoimmune diseases. The cells have numerous features that make them distinct from conventional T cells including their ability to release copious amounts of cytokines following primary activation, a highly restricted TCR repertoire, an activated or memory phenotype, expression of receptors typical of NK cells and unequal distribution in peripheral tissues, to name a few. Definitive proof that iNKT cells develop in the thymus has only recently been established. Little is known about the early development of these cells other than that it appears to be distinct from conventional T cell development. We propose to study several aspects of iNKT cell development ranging from an analysis of the TCR to a study of downstream signaling events in an effort to understand and potentially manipulate the development of these cells. We will first characterize properties of the unusual interaction of the iNKTCR with CD1d to learn how the biology of this remarkably strong TCR-ligand interaction helps define the function of iNKT cells. In Aim 2 we propose to analyze the critical and possibly unique function of the Src-family protein kinase, Fyn in iNKT cell development. The studies of Fyn will guide our search for a proposed second receptor that we believe is required for iNKT cell development. This work will also seek to modulate iNKT cell function by controlling aspects of their development in the thymus. Finally, in Aim 3, we will develop a method to tag developing iNKT cells very early in their development, perhaps prior to cell surface expression of the TCR. This approach will give us a tool to characterize and explore the mechanisms underlying iNKT cell development. Overall, these studies will contribute to our basic understanding of several critical aspects of iNKT cell biology. Understanding key aspects of iNKT cell development will eventually make it possible to alter the function of these cells using gene therapy approaches in an effort to control cancer and other diseases.