: How an undifferentiated precursor cell decides to develop into one lineage over others when faced with multiple developmental options is a question that is central to developmental biology. Generation of two distinct types of T cells, gamma delta and alpha beta T cells, from a pool of bipotential precursor cells is a highly regulated developmental process that involves a precise control of gene expression. Subversion of the normal developmental gene expression patterns results in cell death or uncontrolled cell growth. Hence, understanding normal T cell developmental processes holds the key to identifying rogue genes involved in leukemogenesis and the development of highly specific and novel clinical treatment regiments. This project is aimed at elucidating the mechanism of T cell lineage development from a common precursor. Experiments will be performed to identify gamma delta or alpha beta lineage-committed precursor subset in the thymus by determining the developmental potential of a single precursor cell in fetal thymic organ cultures and by engineering an in vivo reporter which faithfully reflects a lineage-specific trait that can be used as a marker for purifying lineage-committed precursors. Extrinsic factors influencing the lineage commitment will also be examined. It is proposed that two related factors, interleukin-7 (IL-7) and IL- 15, and their downstream intracellular signaling molecules, are critical for T cell maturation and function by controlling the expression of T cell receptor (TCR) gamma genes. To test this working model the role of IL- 15 in controlling TCRgamma locus accessibility, TCRgamma gene transcription and rearrangement will be determined using mice deficient in IL-15 and mice over-expressing IL-15. Intracellular signaling components of IL-7 and IL-15 involved in modulating the TCRgamma locus will be characterized by assaying T cell development in mice with deficiencies in known signaling intermediates and by identifying novel genes critical for IL-7 function in developing gamma delta T cells using a genome-wide differential gene expression profiling. The long-term objective of this application is to identify genes that determine T cell lineage fate.
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